Skip to main content

Advertisement

SpringerLink
Log in

Rationale and Design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (The POSEIDON-DCM Study)

A phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cell vs. Allogeneic Mesenchymal Stem Cells in Patients with Non-ischemic Dilated Cardiomyopathy

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

Abstract

While accumulating clinical trials have focused on the impact of cell therapy in patients with acute myocardial infarction (MI) and ischemic cardiomyopathy, there are fewer efforts to examine cell-based therapy in patients with non-ischemic cardiomyopathy (NICM). We hypothesized that cell therapy could have a similar impact in NICM. The POSEIDON-DCM trial is a phase I/II trial designed to address autologous vs. allogeneic bone marrow-derived mesenchymal stem cells (MSCs) in patients with NICM. In this study, cells will be administered transendocardially with the NOGA injection-catheter system to patients (n = 36) randomly allocated to two treatment groups: group 1 (n = 18 auto-human mesenchymal stem cells (hMSC)) and group 2 (n = 18 allo-hMSCs). The primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCS vs. auto-hMSCs in patients with NICM. This study will establish safety of transendocardial injection of stem cells (TESI), compare phenotypic outcomes, and offer promising advances in the field of cell-based therapy in patients with NICM.

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
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hare, J. M. (2011). The dilated, restrictive and infiltrative cardiomyopathies. In R. O. M. D. L. Bonow, D. P. Zipes, & P. Libby (Eds.), Braunwald’s Heart Disease: a textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier.

    Google Scholar 

  2. Hare, J. M., Walford, G. D., Hruban, R. H., Hutchins, G. M., Deckers, J. W., & Baughman, K. L. (1992). Ischemic cardiomyopathy: endomyocardial biopsy and ventriculographic evaluation of patients with congestive heart failure, dilated cardiomyopathy and coronary artery disease. Journal of the American College of Cardiology, 20, 1318–1325.

    Article  CAS  PubMed  Google Scholar 

  3. Hare, J. M., Traverse, J. H., Henry, T. D., Dib, N., Strumpf, R. K., Schulman, S. P., et al. (2009). A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology, 54, 2277–2286.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Heldman, A. W., DiFede, D. L., Fishman, J. E., Zambrano, J. P., Trachtenberg, B. H., Karantalis, V., et al. (2014). Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA, 311, 62–73.

    Article  CAS  PubMed  Google Scholar 

  5. Yousef, M., Schannwell, C. M., Kostering, M., Zeus, T., Brehm, M., & Strauer, B. E. (2009). The balance study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. Journal of the American College of Cardiology, 53, 2262–2269.

    Article  PubMed  Google Scholar 

  6. Vrtovec, B., Poglajen, G., Lezaic, L., Sever, M., Domanovic, D., Cernelc, P., et al. (2013). Effects of intracoronary cd34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circulation Research, 112, 165–173.

    Article  CAS  PubMed  Google Scholar 

  7. Hare, J. M., Fishman, J. E., Gerstenblith, G., DiFede Velazquez, D. L., Zambrano, J. P., Suncion, V. Y., 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.

    Article  CAS  PubMed  Google Scholar 

  8. Da Silva, J. S., & Hare, J. M. (2013). Cell-based therapies for myocardial repair: emerging role for bone marrow-derived mesenchymal stem cells (MSCs) in the treatment of the chronically injured heart. Methods in Molecular Biology, 1037, 145–163.

    Article  PubMed  Google Scholar 

  9. Thygesen, K., Alpert, J. S., Jaffe, A. S., Simoons, M. L., Chaitman, B. R., White, H. D., et al. (2012). Third universal definition of myocardial infarction. Journal of the American College of Cardiology, 60, 1581–1598.

    Article  PubMed  Google Scholar 

  10. Sasaki, T., Miller, C. F., Hansford, R., Zipunnikov, V., Zviman, M. M., Marine, J. E., et al. (2013). Impact of nonischemic scar features on local ventricular electrograms and scar-related ventricular tachycardia circuits in patients with nonischemic cardiomyopathy. Circulatory Arrhythmia Electrophysiol, 6, 1139–1147.

    Article  Google Scholar 

  11. D’Amario, D., Fiorini, C., Campbell, P. M., Goichberg, P., Sanada, F., Zheng, H., et al. (2011). Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies. Circulation Research, 108, 857–861.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Bolli, R., Chugh, A. R., D’Amario, D., Loughran, J. H., Stoddard, M. F., Ikram, S., et al. (2011). Cardiac stem cells in patients with ischaemic cardiomyopathy (scipio): initial results of a randomised phase 1 trial. Lancet, 378, 1847–1857.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Heidecker, B., Lamirault, G., Kasper, E. K., Wittstein, I. S., Champion, H. C., Breton, E., et al. (2010). The gene expression profile of patients with new-onset heart failure reveals important gender-specific differences. European Heart Journal, 31, 1188–1196.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Amado, L. C., Saliaris, A. P., Schuleri, K. H., St John, M., Xie, J. S., Cattaneo, S., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 102, 11474–11479.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Amado, L. C., Schuleri, K. H., Saliaris, A. P., Boyle, A. J., Helm, R., Oskouei, B., et al. (2006). Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. Journal of the American College of Cardiology, 48, 2116–2124.

    Article  PubMed  Google Scholar 

  16. Parakh, K., Kittleson, M. M., Heidecker, B., Wittstein, I. S., Judge, D. P., Champion, H. C., et al. (2012). The variable natural history of idiopathic dilated cardiomyopathy. Israel Medical Association Journal : IMAJ, 14, 666–671.

    PubMed  Google Scholar 

  17. Hare, J. M. (2008). The etiologic basis of congestive heart failure. In W. S. Colucci (Ed.), Atlas of Heart Failure (pp. 29–56). Philadelphia: Springer.

    Google Scholar 

  18. Owan, T. E., Hodge, D. O., Herges, R. M., Jacobsen, S. J., Roger, V. L., & Redfield, M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of Medicine, 355, 251–259.

    Article  CAS  PubMed  Google Scholar 

  19. Levy, W. C., Mozaffarian, D., Linker, D. T., Sutradhar, S. C., Anker, S. D., Cropp, A. B., et al. (2006). The Seattle heart failure model: prediction of survival in heart failure. Circulation, 113, 1424–1433.

    Article  PubMed  Google Scholar 

  20. Heidecker, B., Kasper, E. K., Wittstein, I. S., Champion, H. C., Breton, E., Russell, S. D., et al. (2008). Transcriptomic biomarkers for individual risk assessment in new-onset heart failure. Circulation, 118, 238–246.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Heidecker, B., Kittleson, M. M., Kasper, E. K., Wittstein, I. S., Champion, H. C., Russell, S. D., et al. (2011). Transcriptomic biomarkers for the accurate diagnosis of myocarditis. Circulation, 123, 1174–1184.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Martino, H. F., Oliveira, P. S., Souza, F. C., Costa, P. C., Assuncao, E. S. E., Villela, R., et al. (2010). A safety and feasibility study of cell therapy in dilated cardiomyopathy. Brazilian Journal of Medical and Biological Research, 43, 989–995.

    Article  CAS  PubMed  Google Scholar 

  23. Freyman, T., Polin, G., Osman, H., Crary, J., Lu, M., Cheng, L., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal, 27, 1114–1122.

    Article  PubMed  Google Scholar 

  24. Perin, E. C., Silva, G. V., Assad, J. A., Vela, D., Buja, L. M., Sousa, A. L., et al. (2008). Comparison of intracoronary and transendocardial delivery of allogeneic mesenchymal cells in a canine model of acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 44, 486–495.

    Article  CAS  PubMed  Google Scholar 

  25. Perin, E. C., Silva, G. V., Fernandes, M. R., Munger, T., Pandey, A., Sehra, R., et al. (2007). First experience with remote left ventricular mapping and transendocardial cell injection with a novel integrated magnetic navigation-guided electromechanical mapping system. EuroIntervention : Journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 3, 142–148.

    Google Scholar 

  26. Mathiasen, A. B., Jorgensen, E., Qayyum, A. A., Haack-Sorensen, M., Ekblond, A., & Kastrup, J. (2012). Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells in chronic ischemic heart failure (MSC-HF trial). American Heart Journal, 164, 285–291.

    Article  PubMed  Google Scholar 

  27. Duran, J. M., Taghavi, S., Berretta, R. M., Makarewich, C. A., Sharp Iii, T., Starosta, T., et al. (2012). A characterization and targeting of the infarct border zone in a swine model of myocardial infarction. Clinical and Translational Science, 5, 416–421.

    Article  CAS  PubMed  Google Scholar 

  28. Kharlamov, A. N., Duckers, H. J., van Beusekom, H. M., Smits, P. C., Perin, E. C., & Serruys, P. W. (2013). Do we have a future with transcatheter adventitial delivery of stem cells? International Journal of Cardiology, 165, 217–221.

    Article  PubMed  Google Scholar 

  29. Dib, N., Dinsmore, J., Lababidi, Z., White, B., Moravec, S., Campbell, A., et al. (2009). One-year follow-up of feasibility and safety of the first U.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAuSMIC study). Journal of the American College of Cardiology: Cardiovascular Interventions, 2, 9–16.

    Google Scholar 

  30. Smits, P. C., Nienaber, C., Colombo, A., Ince, H., Carlino, M., Theuns, D. A., et al. (2006). Myocardial repair by percutaneous cell transplantation of autologous skeletal myoblast as a standalone procedure in post myocardial infarction chronic heart failure patients. EuroIntervention: Journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 1, 417–424.

    Google Scholar 

  31. Smits, P. C., van Geuns, R. J., Poldermans, D., Bountioukos, M., Onderwater, E. E., Lee, C. H., et al. (2003). Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. Journal of the American College of Cardiology, 42, 2063–2069.

    Article  PubMed  Google Scholar 

  32. 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 

  33. Quevedo, H. C., Hatzistergos, K. E., Oskouei, B. N., Feigenbaum, G. S., Rodriguez, J. E., Valdes, D., et al. (2009). Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America, 106, 14022–14027.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Singla DK, Abdelli LS. (2014). Embryonic stem cells and released factors stimulate c-kit/flk-1 progenitor cells and promote neovascularization in doxorubicin-induced cardiomyopathy. Cell Transplant.

  35. Rupp, S., Bauer, J., von Gerlach, S., Fichtlscherer, S., Zeiher, A. M., Dimmeler, S., et al. (2012). Pressure overload leads to an increase of cardiac resident stem cells. Basic Research in Cardiology, 107, 252.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

All authors have provided the corresponding author with written permission to be named in the manuscript. They all have reviewed and approved the final version of the manuscript. The authors are solely responsible for the design and conduct of the study, interpretation of the data, and the contents of the article. The authors would like to thank Dr. Cristina Sanina for her artistic contribution, Mark Martin and Jonathan Wong, who are employees of Biologics Delivery Systems, Cordis Corporation (Irwindale, CA) for their figure contributions, and Dr. Mendizabal, who is an employee of the EMMES Corporation. No human or animal studies were carried out by the authors for this article.

Funding

This study has been funded by NIH grant 5R01HL110737 to J.M.H. and the Starr Foundation. This trial is listed at clinicaltrials.gov (NCT01392625).

Conflict of Interest

Drs. Hare and Heldman report equity interest in Vestion Inc.. Dr. Hare is a consultant to Kardia and holds equity in Heart Genomics.

Author Contributions

Dr. Mushtaq is responsible for manuscript writing. Ms. DiFede is responsible for conception and design and manuscript writing. Dr. Golpanian is responsible for manuscript writing and final approval of the manuscript. Dr. Khan is responsible for conception and design. Dr. Gomes is responsible for conception and design. Dr. Mendizabal is responsible for conception and design. Dr. Heldman is responsible for conception and design. Dr. Hare is responsible for conception and design, final approval of the manuscript, and financial support.

Author information

Authors and Affiliations

  1. Interdisciplinary Stem Cell Institute, Biomedical Research Building, University of Miami Miller School of Medicine, 1501 NW 10th Avenue (Suite 909), Miami, FL, 33136, USA

    Muzammil Mushtaq, Darcy L. DiFede, Samuel Golpanian, Aisha Khan, Samirah A. Gomes, Alan W. Heldman & Joshua M. Hare

  2. Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Muzammil Mushtaq, Alan W. Heldman & Joshua M. Hare

  3. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Samuel Golpanian

  4. The EMMES Corporation, Rockville, MD, 20850, USA

    Adam Mendizabal

Authors
  1. Muzammil Mushtaq
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darcy L. DiFede
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel Golpanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aisha Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samirah A. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adam Mendizabal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alan W. Heldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joshua M. Hare
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joshua M. Hare.

Additional information

Editor-in-Chief Jennifer L. Hall 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

Mushtaq, M., DiFede, D.L., Golpanian, S. et al. Rationale and Design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (The POSEIDON-DCM Study). J. of Cardiovasc. Trans. Res. 7, 769–780 (2014). https://doi.org/10.1007/s12265-014-9594-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-014-9594-0

Keywords

Search

Navigation