Skip to main content
SpringerLink
Log in

Endomyocardial Implantation of Autologous Bone Marrow Mononuclear Cells in Advanced Ischemic Heart Failure: a Randomized Placebo-Controlled Trial (END-HF)

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Prior studies suggest that endomyocardial implantation of autologous bone marrow (BM) mononuclear cell therapy improves symptoms and left ventricular (LV) function in patients with refractory angina; however, the therapeutic efficacy in patients with ischemic cardiomyopathy is unclear. In a randomized, double-blind, placebo-controlled trial, 28 patients with advanced ischemic cardiomyopathy [New York Heart Association III-IV, LV ejection fraction (LVEF) <40 %] were assigned in 2:1 ratio to receive endomyocardial injection of BM cells (100 million, n = 19) or placebo (n = 9), guided by electroanatomical mapping. After 6 months, there was no significant difference between the two groups in LV ejection fraction (LVEF) and LV end-systolic volume (LVESV), LV infarct volume, and LV peri-infarct ischemic volume as determined by cardiac magnetic resonance imaging or exercise capacity. In conclusion, endomyocardial implantation of autologous BM mononuclear cells did not improve LV function or remodeling in patients with advanced ischemic cardiomyopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., Bravata, D. M., Dai, S., Ford, E. S., Fox, C. S., Franco, S., Fullerton, H. J., Gillespie, C., Hailpern, S. M., Heit, J. A., Howard, V. J., Huffman, M. D., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Magid, D., Marcus, G. M., Marelli, A., Matchar, D. B., McGuire, D. K., Mohler, E. R., Moy, C. S., Mussolino, M. E., Nichol, G., Paynter, N. P., Schreiner, P. J., Sorlie, P. D., Stein, J., Turan, T. N., Virani, S. S., Wong, N. D., Woo, D., & Turner, M. B. (2013). American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation, 127, 143–152.

    Article  PubMed  Google Scholar 

  2. Blecker, S., Paul, M., Taksler, G., Ogedegbe, G., & Katz, S. (2013). Heart failure associated hospitalizations in the United States. Journal of the American College of Cardiology, 61, 1259–1267.

    Article  PubMed  Google Scholar 

  3. McMurray, J. J. (2010). Systolic heart failure. New England Journal of Medicine, 362, 228–238.

    Article  CAS  PubMed  Google Scholar 

  4. Siu, C. W., & Tse, H. F. (2012). Cardiac regeneration: messages from CADUCEUS. Lancet, 379, 870–871.

    Article  PubMed  Google Scholar 

  5. Deutsch, M. A., Sturzu, A., & Wu, S. M. (2013). At a crossroad: cell therapy for cardiac repair. Circulation Research, 112, 884–890.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Mesquita, C. T., Rossi, M. I., Carvalho, A. C., Dutra, H. S., Dohmann, H. J., Silva, G. V., Belém, L., Vivacqua, R., Rangel, F. O., Esporcatte, R., Geng, Y. J., Vaughn, W. K., Assad, J. A., Mesquita, E. T., & Willerson, J. T. (2003). Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation, 107, 2294–2302.

    Article  PubMed  Google Scholar 

  7. Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Silva, G. V., Mesquita, C. T., Belém, L., Vaughn, W. K., Rangel, F. O., Assad, J. A., Carvalho, A. C., Branco, R. V., Rossi, M. I., Dohmann, H. J., & Willerson, J. T. (2004). Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation, 110(11 Suppl 1), II213–II218.

    PubMed  Google Scholar 

  8. Fuchs, S., Kornowski, R., Weisz, G., Satler, L. F., Smits, P. C., Okubagzi, P., Baffour, R., Aggarwal, A., Weissman, N. J., Cerqueira, M., Waksman, R., Serrruys, P., Battler, A., Moses, J. W., Leon, M. B., & Epstein, S. E. (2006). Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. American Journal of Cardiology, 97, 823–829.

    Article  PubMed  Google Scholar 

  9. Losordo, D. W., Schatz, R. A., White, C. J., Udelson, J. E., Veereshwarayya, V., Durgin, M., Poh, K. K., Weinstein, R., Kearney, M., Chaudhry, M., Burg, A., Eaton, L., Heyd, L., Thorne, T., Shturman, L., Hoffmeister, P., Story, K., Zak, V., Dowling, D., Traverse, J. H., Olson, R. E., Flanagan, J., Sodano, D., Murayama, T., Kawamoto, A., Kusano, K. F., Wollins, J., Welt, F., Shah, P., Soukas, P., Asahara, T., & Henry, T. D. (2007). Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation, 115, 3165–3172.

    Article  PubMed  Google Scholar 

  10. Tse, H. F., Thambar, S., Kwong, Y. L., Rowlings, P., Bellamy, G., McCrohon, J., Thomas, P., Bastian, B., Chan, J. K., Lo, G., Ho, C. L., Chan, W. S., Kwong, R. Y., Parker, A., Hauser, T. H., Chan, J., Fong, D. Y., & Lau, C. P. (2007). Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial). European Heart Journal, 28, 2998–3005.

    Article  PubMed  Google Scholar 

  11. van Ramshorst, J., Bax, J. J., Beeres, S. L., Dibbets-Schneider, P., Roes, S. D., Stokkel, M. P., de Roos, A., Fibbe, W. E., Zwaginga, J. J., Boersma, E., Schalij, M. J., & Atsma, D. E. (2009). Intramyocardial bone marrow cell injection for chronic myocardial ischemia. JAMA, 301, 1997–2004.

    Article  PubMed  Google Scholar 

  12. Perin, E. C., Silva, G. V., Henry, T. D., Cabreira-Hansen, M. G., Moore, W. H., Coulter, S. A., Herlihy, J. P., Fernandes, M. R., Cheong, B. Y., Flamm, S. D., Traverse, J. H., Zheng, Y., Smith, D., Shaw, S., Westbrook, L., Olson, R., Patel, D., Gahremanpour, A., Canales, J., Vaughn, W. K., & Willerson, J. T. (2011). A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). American Heart Journal, 161, 1078–1087.

    Article  PubMed  Google Scholar 

  13. Losordo, D. W., Henry, T. D., Davidson, C., Sup Lee, J., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Traverse, J. H., Amrani, D., Ewenstein, B. M., Riedel, N., Story, K., Barker, K., Povsic, T. J., Harrington, R. A., & Schatz, R. A. (2011). ACT34-CMI Investigators. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circulation Research, 109, 428–436.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Perin, E. C., Willerson, J. T., Pepine, C. J., Henry, T. D., Ellis, S. G., Zhao, D. X., Silva, G. V., Lai, D., Thomas, J. D., Kronenberg, M. W., Martin, A. D., Anderson, R. D., Traverse, J. H., Penn, M. S., Anwaruddin, S., Hatzopoulos, A. K., Gee, A. P., Taylor, D. A., Cogle, C. R., Smith, D., Westbrook, L., Chen, J., Handberg, E., Olson, R. E., Geither, C., Bowman, S., Francescon, J., Baraniuk, S., Piller, L. B., Simpson, L. M., Loghin, C., Aguilar, D., Richman, S., Zierold, C., Bettencourt, J., Sayre, S. L., Vojvodic, R. W., Skarlatos, S. I., Gordon, D. J., Ebert, R. F., Kwak, M., Moyé, L. A., Simari, R. D., & Cardiovascular Cell Therapy Research Network (CCTRN). (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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Grothues, F., Smith, G. C., Moon, J. C., Bellenger, N. G., Collins, P., Klein, H. U., & Pennell, D. J. (2002). Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. American Journal of Cardiology, 90, 29–34.

    Article  PubMed  Google Scholar 

  16. Kim, R. J., Wu, E., Rafael, A., Chen, E. L., Parker, M. A., Simonetti, O., Klocke, F. J., Bonow, R. O., & Judd, R. M. (2000). The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. New England Journal of Medicine, 343, 1445–1453.

    Article  CAS  PubMed  Google Scholar 

  17. Chan, C. W., Kwong, Y. L., Kwong, R. Y., Lau, C. P., & Tse, H. F. (2010). Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery disease. Journal of Cardiovascular Magnetic Resonance, 12, 6.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Santoso, T., Siu, C. W., Irawan, C., Chan, C. S., Alwi, I., Yiu, K. H., Azis, A., Kwong, Y. L., Tse, H. F. (2013). A randomized placebo controlled trial of endomyocardial implantation of autologous bone marrow mononuclear cells in advanced ischemic heart failure (END-HF). European Heart Journal, 34(suppl 1). doi:10.1093/eurheartj/eht309.3554.

  19. Tse, H. F., Wong, K. K., Siu, C. W., Zhang, X. H., Ho, W. Y., & Lau, C. P. (2009). Upgrading pacemaker patients with right ventricular apical pacing to right ventricular septal pacing improves left ventricular performance and functional capacity. Journal of Cardiovascular Electrophysiology, 20, 901–905.

    Article  PubMed  Google Scholar 

  20. Laflamme, M. A., & Murry, C. E. (2011). Heart regeneration. Nature, 473, 326–335.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hofmann, M., Wollert, K. C., Meyer, G. P., Menke, A., Arseniev, L., Hertenstein, B., Ganser, A., Knapp, W. H., & Drexler, H. (2005). Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation, 111, 2198–2202.

    Article  PubMed  Google Scholar 

  22. Liao, R., Pfister, O., Jain, M., & Mouquet, F. (2007). The bone marrow—cardiac axis of myocardial regeneration. Progress in Cardiovascular Diseases, 50, 18–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Yiu, K. H., & Tse, H. F. (2014). Specific role of impaired glucose metabolism and diabetes mellitus in endothelial progenitor cell characteristics and function. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 1136–1143.

    Article  CAS  PubMed  Google Scholar 

  24. Vasa, M., Fichtlscherer, S., Aicher, A., Adler, K., Urbich, C., Martin, H., Zeiher, A. M., & Dimmeler, S. (2001). Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circulation Research, 89, E1–E7.

    Article  CAS  PubMed  Google Scholar 

  25. Lai, W. H., Ho, J. C., Chan, Y. C., Ng, J. H., Au, K. W., Wong, L. Y., Siu, C. W., & Tse, H. F. (2013). Attenuation of hind-limb ischemia in mice with endothelial-like cells derived from different sources of human stem cells. PLoS One, 8, e57876.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Poole, J. C., & Quyyumi, A. A. (2013). Progenitor cell therapy to treat acute myocardial infarction: the promise of high-dose autologous CD34(+) bone marrow mononuclear cells. Stem Cells International.

  27. Williams, A. R., & Hare, J. M. (2011). Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation Research, 109, 923–940.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Hare, J. M., Fishman, J. E., Gerstenblith, G., DiFede Velazquez, D. L., Zambrano, J. P., Suncion, V. Y., Tracy, M., Ghersin, E., Johnston, P. V., Brinker, J. A., Breton, E., Davis-Sproul, J., Schulman, I. H., Byrnes, J., Mendizabal, A. M., Lowery, M. H., Rouy, D., Altman, P., Wong Po Foo, C., Ruiz, P., Amador, A., Da Silva, J., McNiece, I. K., & Heldman, A. W. (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.

    Article  CAS  PubMed  Google Scholar 

  29. Bartunek, J., Behfar, A., Dolatabadi, D., Vanderheyden, M., Ostojic, M., Dens, J., El Nakadi, B., Banovic, M., Beleslin, B., Vrolix, M., Legrand, V., Vrints, C., Vanoverschelde, J. L., Crespo-Diaz, R., Homsy, C., Tendera, M., Waldman, S., Wijns, W., & Terzic, A. (2013). Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. Journal of the American College of Cardiology, 61, 2329–2338.

    Article  PubMed  Google Scholar 

  30. Williams, A. R., Hatzistergos, K. E., Addicott, B., McCall, F., Carvalho, D., Suncion, V., Morales, A. R., Da Silva, J., Sussman, M. A., Heldman, A. W., & Hare, J. M. (2013). Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation, 127, 213–223.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the S.K. Yee Medical Foundation Grant (208207); and Research Grant Council of Hong Kong: General Research Fund (no. HKU 780110M); the Collaborative Research Fund (HKU 8/CRF/09); and Theme Based Research Scheme (T12-705/11).

Disclosures

This study was presented at the European Society of Cardiology Congress 2013 and as a published abstract: Eur Heart J. 2013; 34 (suppl 1): doi: 10.1093/eurheartj/eht309.3554.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Faculty of Medicine, Dr. Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia

    Teguh Santoso, Cosphiadi Irawan & Idrus Alwi

  2. Cardiology Division, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, HKSAR, China

    Ching-Wah Siu, Wing-Sze Chan, Kai-Hang Yiu & Hung-Fat Tse

  3. Dharmais Cancer Hospital, Jakarta, Indonesia

    Auda Aziz

  4. Division of Haematology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, HKSAR, China

    Yok-Lam Kwong

Authors
  1. Teguh Santoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ching-Wah Siu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cosphiadi Irawan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wing-Sze Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Idrus Alwi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kai-Hang Yiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Auda Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yok-Lam Kwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hung-Fat Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hung-Fat Tse.

Additional information

Associate Editor Lorrie Kirshenbaum oversaw the review of this article

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santoso, T., Siu, CW., Irawan, C. et al. Endomyocardial Implantation of Autologous Bone Marrow Mononuclear Cells in Advanced Ischemic Heart Failure: a Randomized Placebo-Controlled Trial (END-HF). J. of Cardiovasc. Trans. Res. 7, 545–552 (2014). https://doi.org/10.1007/s12265-014-9580-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-014-9580-6

Keywords

Search

Navigation