Short CommunicationOpen Access cc icon

Cell administration routes for heart failure: a comparative re-evaluation of the REGENERATE-DCM and REGENERATE-IHD trials

Doo Sun Sim

Daniel A Jones

Ceri Davies

Didier Locca

Jessry Veerapen

Alice Reid

Thomas Godec

John Martin

Anthony Mathur

Doo Sun Sim

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Department of Cardiovascular Medicine, Chonnam National University Hospital, Chonnam National University School of Medicine, Gwanjgu, Republic of Korea

Search for more papers by this author

Daniel A Jones

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Department of Interventional Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK

Search for more papers by this author

Ceri Davies

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Department of Interventional Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK

Search for more papers by this author

Didier Locca

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Search for more papers by this author

Jessry Veerapen

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Department of Interventional Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK

Search for more papers by this author

Alice Reid

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Search for more papers by this author

Thomas Godec

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Barts Cardiovascular Clinical Trials Unit, William Harvey Research Institute, Queen Mary University of London, London, UK

Search for more papers by this author

John Martin

University College London, London, UK

Search for more papers by this author

Anthony Mathur

*Author for correspondence: Tel.: +44 20 3765 8740;

E-mail Address: a.mathur@qmul.ac.uk

https://orcid.org/0000-0001-7941-9653

Centre for Cardiovascular Medicine & Devices, William Harvey Research Institute, Queen Mary University of London, London, UK

Department of Interventional Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK

Search for more papers by this author

Published Online:13 Oct 2022https://doi.org/10.2217/rme-2022-0138

View article

Abstract

Aims: Given the logistical issues surrounding intramyocardial cell delivery, we sought to address the efficacy of the simpler, more accessible intracoronary route by re-evaluating REGENERATE-DCM and REGENERATE-IHD (autologous cell therapy trials for heart failure; n = 150). Methods: A retrospective statistical analysis was performed on the trials' combined data. The following end points were evaluated: left ventricular ejection fraction (LVEF), N-terminal pro brain natriuretic peptide concentration (NT-proBNP), New York Heart Association class (NYHA) and quality of life. Results: This demonstrated a new efficacy signal for intracoronary delivery, with significant benefits to: LVEF (3.7%; p = 0.01), NT-proBNP (median -76 pg/ml; p = 0.04), NYHA class (48% patients; p = 0.01) and quality of life (12 ± 19; p = 0.006). The improvements in LVEF, NYHA and quality of life scores remained significant compared to the control group. Conclusion: The efficacy and logistical simplicity of intracoronary delivery should be taken into consideration for future trials.

Tweetable abstract

The efficacy and logistical simplicity of intracoronary delivery should be considered when planning cell therapy trials.

Graphical abstract

Plain language summary

Trials of cell therapy for heart failure have not clearly identified the best method to deliver the cells to the heart. A small proportion of these studies have used the intracoronary method (which infuses the cells into the heart's arteries) as it was thought to be less effective. However, this is the simplest method and uses widely accessible techniques and equipment. By combining data from two previous heart failure trials, we sought to look for an efficacy signal for the intracoronary method in a larger sample size. We found that the intracoronary route demonstrated improvements in patients' heart function and symptoms. Although it may require a larger number of patients to show efficacy, this signal, alongside the intracoronary route's relative simplicity, should be taken into consideration when future trials of cell therapy for heart failure are planned.

Keywords:

Papers of special note have been highlighted as: • of interest

References

1. MacIntyre K, Capewell S, Stewart S et al. Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation 102(10), 1126–1131 (2000).
Medline CASGoogle Scholar
2. Mosterd A, Cost B, Hoes AW et al. The prognosis of heart failure in the general population: the Rotterdam study. Eur. Heart J. 22(15), 1318–1327 (2001).
Medline CASGoogle Scholar
3. Wang Y, Xu F, Ma J et al. Effect of stem cell transplantation on patients with ischemic heart failure: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res. Ther. 10(1), 125 (2019).
Medline CASGoogle Scholar
4. Jayaraj JS, Janapala RN, Qaseem A et al. Efficacy and safety of stem cell therapy in advanced heart failure patients: a systematic review with a meta-analysis of recent trials between 2017 and 2019. Cureus 11(9), e5585 (2019).
MedlineGoogle Scholar
5. Fisher SA, Doree C, Mathur A et al. Meta-analysis of cell therapy trials for patients with heart failure. Circ. Res. 116(8), 1361–1377 (2015).
Medline CASGoogle Scholar
6. Reid A, Mathur A. Cell-based regenerative therapy. In: The PCR-EAPCI Textbook. Wijns WSerruys PWVahanian AEeckhout EDe Palma Rvan Sambeek M (Eds). Europa Digital and Publishing, Toulouse, France (2021). • A comprehensive summary of cell-based therapies in interventional cardiology which includes delivery route discussions.
Google Scholar
7. Strauer BE, Steinhoff G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J. Am. Coll. Cardiol. 58(11), 1095–1104 (2011).
MedlineGoogle Scholar
8. Hamshere S, Arnous S, Choudhury T et al. Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy: The REGENERATEDCM clinical trial. Eur. Heart J. 36(44), 3061–3069 (2015). • Publication of the REGENERATE-DCM trial results used in this analysis.
Medline CASGoogle Scholar
9. Choudhury T, Mozid A, Hamshere S et al. An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur. J. Heart. Fail. 19(1), 138–147 (2017). • Publication of the REGENERATE-IHD trial results used in this analysis.
Medline CASGoogle Scholar
10. Henry T, Losordo D, Traverse J et al. Autologous CD34⁺ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur. Heart J. 39(23), 2208–2216 (2018).
Medline CASGoogle Scholar
11. Tripathi A, Khan MS, Khan AR et al. Cell therapy for nonischemic dilated cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials. Stem Cells Transl. Med. 10(10), 1394–1405 (2021).
MedlineGoogle Scholar
12. Zhao XF, Xu Y, Zhu ZY et al. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet. Mol. Res. 14(2), 3010–3017 (2015)
Medline CASGoogle Scholar
13. Argüero R, Careaga-Reyna G, Castaño-Guerra R et al. Cellular autotransplantation for ischemic and idiopathic dilated cardiomyopathy. preliminary report. Arch. Med. Res. 37(8), 1010–1014 (2006).
MedlineGoogle Scholar
14. Henry TD, Traverse JH, Hammon BL et al. Safety and efficacy of ixmyelocel-T an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy. Circ. Res. 115(8), 730–737 (2014).
Medline CASGoogle Scholar
15. Bolli R, Perin EC, Willerson JT et al. Allogeneic mesenchymal cell therapy in anthracycline-induced cardiomyopathy heart failure patients: the CCTRN SENECA trial. JACC CardioOncology 2(4), 581–595 (2020).
MedlineGoogle Scholar
16. Arnous S, Mozid A, Mathur A. The bone marrow derived adult stem cells for dilated cardiomyopathy (REGENERATE-DCM) trial: study design. Regen. Med. 6(4), 525–533 (2011).
Google Scholar
17. Yeo C, Mathur A. Autologous bone marrow-derived stem cells for ischemic heart failure: REGENERATE-IHD trial. Regen. Med. 4(1), 119–127 (2009).
Google Scholar
18. Vrtovec B, Poglajen G, Lezaic L et al. Comparison of transendocardial and intracoronary CD34⁺ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 128(Suppl. 11), S42–S49 (2013).
Medline CASGoogle Scholar
19. Fisher SA, Doree C, Mathur A et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 12(12), CD007888 (2016). • A meta-analysis that includes an analysis of efficacy based on delivery route.
MedlineGoogle Scholar
20. Attar A, Bahmanzadegan Jahromi F, Kavousi S et al. Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials. Stem Cell Res. Ther. 12(1), 600 (2021). • Another meta-analysis looking at a different disease state and a different cell type that also did not show any clear superiority between intramyocardial and intracoronary delivery.
Medline CASGoogle Scholar
21. Packer M, Kumbhani DJ, Bhatt DL. Empagliflozin outcome trial in patients with chronic heart failure and a reduced ejection fraction – EMPEROR-Reduced. N. Engl. J. Med. 383(15), 1413–1424 (2020).
Medline CASGoogle Scholar
22. Vrtovec B, Poglajen G, Lezaic L et al. Effects of intracoronary CD34⁺ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ. Res. 112(1), 165–173 (2013).
Medline CASGoogle Scholar
23. Gu X, Xie Y, Gu J et al. Repeated intracoronary infusion of peripheral blood stem cells with G-CSF in patients with refractory ischemic heart failure: a pilot study. Circ. J. 75(4), 955–963 (2011).
MedlineGoogle Scholar
24. Poglajen G, Sever M, Cukjati M et al. Effects of transendocardial CD34⁺ cell transplantation in patients with ischemic cardiomyopathy. Circ. Cardiovasc. Interv. 7(4), 552–559 (2014).
Medline CASGoogle Scholar
25. Vrtovec B, Poglajen G, Sever M et al. Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy. J. Card. Fail. 17(4), 272–281 (2011).
MedlineGoogle Scholar
26. Lezaic L, Socan A, Poglajen G et al. Intracoronary transplantation of CD34⁺ cells is associated with improved myocardial perfusion in patients with nonischemic dilated cardiomyopathy. J. Card. Fail. 21(2), 145–152 (2015).
Medline CASGoogle Scholar
27. Vrtovec B, Poglajen G, Sever M et al. Effects of repetitive transendocardial CD34⁺ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circ. Res. 123(3), 389–396 (2018).
Medline CASGoogle Scholar
28. Bocchi EA, Bacal F, Guimarães G et al. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure. Int. J. Cardiol. 138(1), 94–97 (2010).
MedlineGoogle Scholar

Vol. 17, No. 12

Supplemental Materials

Metrics

Downloaded 644 times

History

Received 4 August 2022

Accepted 21 September 2022

Published online 13 October 2022

Published in print December 2022

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/rme-2022-0138

Author contributions

DS Sim: analysis of data, original draft of the work; DA Jones: interpretation of data, revision of work; C Davies: acquisition of data, revision of work; D Locca: acquisition of data, revision of work; J Veerapen: acquisition of data, revision of work; A Reid: interpretation of data, revision of work; T Godec: analysis of data, revision of work; J Martin: interpretation of data, revision of work; A Mathur: conception and design of work, acquisition and interpretation of data, revision of work. All authors: final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors thank all the staff at the London Chest catheterization laboratories, The Heart Cells Foundation, Barts and the London Charity and Chugai Pharma. The work at UCLH was supported by the UCLH Biomedical Research Centre.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human investigations. In addition, informed consent has been obtained from the participants involved.

Open access

This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

PDF download