title: Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics.
abstract: OBJECTIVE
  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).
authors.affiliation: Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium. jozef.bartunek@olvz-aalst.be
authors.forename: Jozef
authors.initials: J
authors.lastname: Bartunek
authors.forename: Atta
authors.initials: A
authors.lastname: Behfar
authors.forename: Dariouch
authors.initials: D
authors.lastname: Dolatabadi
authors.forename: Marc
authors.initials: M
authors.lastname: Vanderheyden
authors.forename: Miodrag
authors.initials: M
authors.lastname: Ostojic
authors.forename: Jo
authors.initials: J
authors.lastname: Dens
authors.forename: Badih
authors.initials: B
authors.lastname: El Nakadi
authors.forename: Marko
authors.initials: M
authors.lastname: Banovic
authors.forename: Branko
authors.initials: B
authors.lastname: Beleslin
authors.forename: Mathias
authors.initials: M
authors.lastname: Vrolix
authors.forename: Victor
authors.initials: V
authors.lastname: Legrand
authors.forename: Christian
authors.initials: C
authors.lastname: Vrints
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.forename: Ruben
authors.initials: R
authors.lastname: Crespo-Diaz
authors.forename: Christian
authors.initials: C
authors.lastname: Homsy
authors.forename: Michal
authors.initials: M
authors.lastname: Tendera
authors.forename: Scott
authors.initials: S
authors.lastname: Waldman
authors.forename: William
authors.initials: W
authors.lastname: Wijns
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006333:Heart Failure / Q000175:diagnosis / Q000401:mortality* / Q000628:therapy*; D006334:Heart Function Tests; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008875:Middle Aged; D011446:Prospective Studies; D012016:Reference Values; D018570:Risk Assessment; D013318:Stroke Volume / Q000502:physiology; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology*