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.
Similar content being viewed by others
Change history
18 February 2020
Editor's Note: The Editor-in-Chief is currently investigating this article (Anastasiadis et al. 2016) as concerns have been raised about the ethics and regulatory approvals related to the cells used in the research. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.
19 October 2020
A Correction to this paper has been published: https://doi.org/10.1007/s12265-020-10076-7
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
References
Braunwald, E. (2013). Heart failure. Journal of the American College of Cardiology Heart Failure, 1, 1–20.
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.
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.
Oka, T., & Komuro, I. (2008). Molecular mechanisms underlying the transition of cardiac hypertrophy to heart failure. Circulation Journal, 72(Suppl. A), A13–A16.
Gheorghiade, M., & Bonow, R. O. (1998). Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation, 97, 282–289.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research, 103, 1204–1219.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Associate Editor Enrique Lara-Pezzi oversaw the review of this article
Rights and permissions
About this article
Cite this article
Anastasiadis, K., Antonitsis, P., Westaby, S. et al. 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. J. of Cardiovasc. Trans. Res. 9, 202–213 (2016). https://doi.org/10.1007/s12265-016-9686-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12265-016-9686-0