Cardiopoietic stem cell therapy in heart failure: The C-CURE (cardiopoietic stem cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics

Jozef Bartunek, Atta Behfar, Dariouch Dolatabadi, Marc Vanderheyden, Miodrag Ostojic, Jo Dens, Badih El Nakadi, Marko Banovic, Branko Beleslin, Mathias Vrolix, Victor Legrand, Christian Vrints, Jean Louis Vanoverschelde, Ruben Crespo-Diaz, Christian Homsy, Michal Tendera, Scott Waldman, William Wijns, Andre Terzic

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396 Scopus citations

Abstract

Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238).

Original languageEnglish (US)
Pages (from-to)2329-2338
Number of pages10
JournalJournal of the American College of Cardiology
Volume61
Issue number23
DOIs
StatePublished - Jun 11 2013
Externally publishedYes

Bibliographical note

Funding Information:
The study was supported by the National Institutes of Health, Marriott Heart Disease Research Program and Center for Regenerative Medicine, Mayo Clinic ; Ministry of Education and Science of Serbia ; Cardio3 BioSciences ; Walloon Region General Directorate for Economy, Employment, and Research ; and Meijer Lavino Foundation for Cardiac Research Aalst . Dr. Bartunek reports that the honoraria for lectures and consulting fees that he receives from several pharmaceutical and device companies go to the Cardiovascular Research Center Aalst. The Cardiovascular Research Center Aalst is a co-founder of Cardio3 BioSciences. Dr. Behfar has received research grants and travel support from Cardio3 BioSciences and the National Institutes of Health . Dr. Vanderheyden reports that the honoraria for lectures and consulting fees that he receives from several pharmaceutical and device companies go to the Cardiovascular Research Center Aalst. Dr. Vanoverschelde has received investigator fees from Cardio3 BioSciences . Dr. Homsy owns shares in Cardio3 BioSciences. Dr. Waldman receives consultant fees as the Chair of the DSMB for the C-Cure Trial sponsored by Cardio3 BioSciences . Dr. Wijns reports that the honoraria for lectures and consulting fees that he receives from several pharmaceutical and device companies go to the Cardiovascular Research Center Aalst. Dr. Terzic receives research grants from Cardio3 Biosciences and the National Institutes of Health . Drs. Behfar and Terzic received Mayo Clinic–administered research grants from the National Institutes of Health and Cardio3 BioSciences . Mayo Clinic has rights to future royalties from Cardio3 BioSciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Keywords

  • bone marrow
  • cardiopoiesis
  • ischemic cardiomyopathy
  • regeneratrive medicine
  • stem cells

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