Advertisement

Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial

  • Kyriakos Anastasiadis
  • Polychronis AntonitsisEmail author
  • Stephen Westaby
  • Ajan Reginald
  • Sabena Sultan
  • Argirios Doumas
  • George Efthimiadis
  • Martin John Evans
Original Article

Abstract

Heart failure is a life-limiting condition affecting over 40 million patients worldwide. Ischemic cardiomyopathy (ICM) is the most common cause. This study investigates in situ cardiac regeneration utilizing precision delivery of a novel mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ischemic cardiomyopathy (LVEF < 40 %). The phase IIa safety study was designed to enroll 11 patients. Preoperative scintigraphy imaging (SPECT) was used to identify hibernating myocardium not suitable for conventional myocardial revascularization for iMP implantation. iMP cells were implanted intramyocardially in predefined viable peri-infarct areas that showed poor perfusion, which could not be grafted due to poor target vessel quality. Postoperatively, SPECT was then used to identify changes in scar area. Intramyocardial implantation of iMP cells with CABG was safe with preliminary evidence of efficacy of improved myocardial contractility and perfusion of nonrevascularized territories resulting in a significant reduction in left ventricular scar area at 12 months after treatment. Clinical improvement was associated with a significant improvement in quality of life at 6 months posttreatment in all patients. The results suggest the potential for in situ myocardial regeneration in ischemic heart failure by delivery of iMP cells.

Keywords

Ischemic cardiomyopathy Coronary artery bypass grafting Stem cells Allogeneic Mesenchymal Heart failure 

Abbreviations

CABG

Coronary artery bypass grafting

ICM

Ischemic cardiomyopathy

IRB

Institutional review board

LAL

Limulus amebocyte lysate

LV

Left ventricular

LVEF

Left ventricular ejection fraction

MACCE

Major adverse cardiac and cerebrovascular events

MHC

Major histocompatibility class

MLHFQ

Minnesota Living with Heart Failure Questionnaire

MMP

Matrix metalloproteinase

MSC

Mesenchymal stem cells

NYHA

New York Heart Association

PCR

Polymerase chain reaction

SPECT

Single photon emission computed tomography

TIMP

Tissue inhibitor of matrix metalloproteinase

Notes

Acknowledgments

We would like to thank the molecular biologist Dr Nancy Piouka for her valuable contribution in the preparation and handling of the iMP cells.

Compliance with Ethical Standards

Sources of Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Disclosures

AR, MJE, and SS hold shares in Cell Therapy Limited.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Braunwald, E. (2013). Heart failure. Journal of the American College of Cardiology Heart Failure, 1, 1–20.Google Scholar
  2. 2.
    Moran, A. E., Tzong, K. Y., Forouzanfar, M. H., et al. (2014). Variations in ischemic heart disease burden by age, country, and income: the global burden of diseases, injuries and risk factors 2010 study. Global Heart, 9, 91–99.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ammar, K. A., Jacobsen, S. J., Mahoney, D. W., et al. (2007). Heart failure prevalence and prognostic significance of heart failure stages. Application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circulation, 115, 1563–1570.CrossRefPubMedGoogle Scholar
  4. 4.
    Oka, T., & Komuro, I. (2008). Molecular mechanisms underlying the transition of cardiac hypertrophy to heart failure. Circulation Journal, 72(Suppl. A), A13–A16.CrossRefPubMedGoogle Scholar
  5. 5.
    Gheorghiade, M., & Bonow, R. O. (1998). Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation, 97, 282–289.CrossRefPubMedGoogle Scholar
  6. 6.
    Stamm, C., Kleine, H. D., Choi, Y. H., et al. (2007). Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. Journal of Thoracic and Cardiovascular Surgery, 133, 717–725.CrossRefPubMedGoogle Scholar
  7. 7.
    Santoso, T., Siu, C. W., Irawan, C., et al. (2014). Endomyocardial implantation of autologous bone marrow mononuclear cells in advanced ischemic heart failure: a randomized placebo-controlled trial (END-HF). Journal of Cardiovascular Translational Research, 7, 545–552.CrossRefPubMedGoogle Scholar
  8. 8.
    Afzal, M. R., Samanta, A., Shah, Z. I., et al. (2015). Adult bone marrow cell therapy for ischemic heart disease: evidence and insights from randomized controlled trials. Circulation Research, 117, 558–575.CrossRefPubMedGoogle Scholar
  9. 9.
    Heldman, A. W., DiFede, D. L., Fishman, J. E., et al. (2014). Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA, 311, 62–73.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fisher, S. A., Brunskill, S. J., Doree, C., Mathur, A., Taggart, D. P., & Martin-Rendon, E. (2014). Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database of Systematic Reviews, 4, CD007888.PubMedGoogle Scholar
  11. 11.
    Dominici, M., Le Blanc, K., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.CrossRefPubMedGoogle Scholar
  12. 12.
    Hillis, L. D., Smith, P. K., Anderson, J. L., et al. (2011). American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; Society of Cardiovascular Anesthesiologists; Society of Thoracic Surgeons. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. Journal of the American College of Cardiology, 58, e123–e210.CrossRefPubMedGoogle Scholar
  13. 13.
    Schuleri, K. H., Feigenbaum, G. S., Centola, M., et al. (2009). Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. European Heart Journal, 30, 2722–2732.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chiesa, S., Morbelli, S., Morando, S., et al. (2011). Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proceedings of the National Academy of Sciences of the United States of America, 108, 17384–17389.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Houtgraaf, J. H., de Jong, R., Kazemi, K., et al. (2013). Intracoronary infusion of allogeneic mesenchymal precursor cells directly after experimental acute myocardial infarction reduces infarct size, abrogates adverse remodeling, and improves cardiac function. Circulation Research, 113, 153–166.CrossRefPubMedGoogle Scholar
  16. 16.
    Le Blanc, K., Tammik, C., Rosendahl, K., et al. (2003). HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Experimental Hematology, 31, 890–896.CrossRefPubMedGoogle Scholar
  17. 17.
    Klyushnenkova, E., Mosca, J. D., Zernetkina, V., et al. (2005). T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. Journal of Biomedical Science, 12, 47–57.CrossRefPubMedGoogle Scholar
  18. 18.
    Perin, E. C., Willerson, J. T., Pepine, C. J., et al. (2012). Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA, 307, 1717–1726.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hare, J. M., Fishman, J. E., Gerstenblith, G., et al. (2012). Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA, 308, 2369–2379.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fraser, J. K., Hicok, K. C., Shanahan, R., et al. (2014). The Celution® system: automated processing of adipose-derived regenerative cells in a functionally closed system. Advances in Wound Care (New Rochelle), 3, 38–45.CrossRefGoogle Scholar
  21. 21.
    Zhang, D., Fan, G. C., Zhou, X., et al. (2008). Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology, 44, 281–292.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Liang, J., Huang, W., Yu, X., et al. (2012). Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4)). PLoS One, 7, e46158.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Huang, W., Wang, T., Zhang, D., et al. (2012). Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. Stem Cells and Development, 21, 778–789.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Karantalis, V., DiFede, D. L., Gerstenblith, G., et al. (2014). Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial. Circulation Research, 114, 1302–1310.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dib, N., Khawaja, H., Varner, S., et al. (2011). Cell therapy for cardiovascular disease: a comparison of methods of delivery. Journal of Cardiovascular Translational Research, 4, 177–181.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hou, D., Youssef, E. A., Brinton, T. J., et al. (2005). Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation, 112(Suppl I), I150–I156.PubMedGoogle Scholar
  27. 27.
    Bolli, R., Chugh, A. R., D’Amario, D., et al. (2011). Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet, 378, 1847–1857.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Donndorf, P., Kaminski, A., Tiedemann, G., Kundt, G., & Steinhoff, G. (2012). Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials, 13, 99.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Franchi, F., Ezenekwe, A., Wellkamp, L., Peterson, K. M., Lerman, A., & Rodriguez-Porcel, M. (2014). Renin inhibition improves the survival of mesenchymal stromal cells in a mouse model of myocardial infarction. Journal of Cardiovascular Translational Research, 7, 560–569.CrossRefPubMedGoogle Scholar
  30. 30.
    Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research, 107, 913–922.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research, 103, 1204–1219.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kinnaird, T., Stabile, E., Burnett, M. S., et al. (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research, 94, 678–685.CrossRefPubMedGoogle Scholar
  33. 33.
    Xiong, Q., Ye, L., Zhang, P., et al. (2012). Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells. Circulation Research, 111, 455–468.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mathiasen, A. B., Qayyum, A. A., Jørgensen, E., et al. (2015). Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). European Heart Journal, 36, 1744–1753.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kyriakos Anastasiadis
    • 1
  • Polychronis Antonitsis
    • 1
    Email author
  • Stephen Westaby
    • 2
  • Ajan Reginald
    • 3
  • Sabena Sultan
    • 2
  • Argirios Doumas
    • 4
  • George Efthimiadis
    • 5
  • Martin John Evans
    • 6
  1. 1.Cardiothoracic DepartmentAHEPA University HospitalThessalonikiGreece
  2. 2.The John Radcliffe HospitalOxford University HospitalsOxfordUK
  3. 3.Experimental TherapeuticsUniversity of OxfordOxfordUK
  4. 4.Department of Nuclear Medicine, AHEPA University HospitalAristotle University of ThessalonikiThessalonikiGreece
  5. 5.First Cardiology DepartmentAHEPA University HospitalThessalonikiGreece
  6. 6.School of BiosciencesCardiff UniversityWalesUK

Personalised recommendations