title: Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.
abstract: BACKGROUND
  Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.
  
  
  OBJECTIVE
  To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.
  
  
  RESULTS
  Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).
  
  
  CONCLUSIONS
  Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.
  
  
  BACKGROUND
  http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.
authors.affiliation: From the University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL (V.K., D.L.D., R.S., M.M., V.Y.S., A.W.L., J.M.H.); Johns Hopkins University, Cardiovascular Division, Baltimore, MD (G.G., S.S., E.B., J.D.-S., A.C.L.); University of Maryland, Cardiothoracic Surgery, Baltimore, MD (S.P., J.C.); Veterans Affairs Healthcare System, Cardiothoracic Surgery, Miami, FL (J.S., T.Z.K.); Jackson Health System, Cardiology, Miami, FL (J.P.Z.); University of Miami Miller School of Medicine, Radiology, Miami, FL (J.F., P.P.); University of Texas MD Anderson, Stem Cell Transplantation, Houston, TX (I.M.N.), Johns Hopkins University, Heart and Vascular Institute, Baltimore, MD (K.W.), Johns Hopkins University, Comprehensive Transplant Center (A.S.); University of Southern California, Internal Medicine, Los Angeles, CA (G.F.); Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (I.B.); EMMES Corporation, Rockville, MD (A.M.), University of Miami Miller School of Medicine, Hematology/Oncology, Miami, FL (J.B.); and University of Miami Miller School of Medicine, Cardiology, Miami, FL (T.Z.K., M.L.).
authors.forename: Vasileios
authors.initials: V
authors.lastname: Karantalis
authors.forename: Darcy L
authors.initials: DL
authors.lastname: DiFede
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.forename: Si
authors.initials: S
authors.lastname: Pham
authors.forename: James
authors.initials: J
authors.lastname: Symes
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Zambrano
authors.forename: Joel
authors.initials: J
authors.lastname: Fishman
authors.forename: Pradip
authors.initials: P
authors.lastname: Pattany
authors.forename: Ian
authors.initials: I
authors.lastname: McNiece
authors.forename: John
authors.initials: J
authors.lastname: Conte
authors.forename: Steven
authors.initials: S
authors.lastname: Schulman
authors.forename: Katherine
authors.initials: K
authors.lastname: Wu
authors.forename: Ashish
authors.initials: A
authors.lastname: Shah
authors.forename: Elayne
authors.initials: E
authors.lastname: Breton
authors.forename: Janice
authors.initials: J
authors.lastname: Davis-Sproul
authors.forename: Richard
authors.initials: R
authors.lastname: Schwarz
authors.forename: Gary
authors.initials: G
authors.lastname: Feigenbaum
authors.forename: Muzammil
authors.initials: M
authors.lastname: Mushtaq
authors.forename: Viky Y
authors.initials: VY
authors.lastname: Suncion
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lardo
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.forename: Adam
authors.initials: A
authors.lastname: Mendizabal
authors.forename: Tomer Z
authors.initials: TZ
authors.lastname: Karas
authors.forename: John
authors.initials: J
authors.lastname: Byrnes
authors.forename: Maureen
authors.initials: M
authors.lastname: Lowery
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D009202:Cardiomyopathies / Q000628:therapy*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002921:Cicatrix / Q000473:pathology / Q000628:therapy; D001026:Coronary Artery Bypass; D005355:Fibrosis / Q000473:pathology / Q000628:therapy; D005500:Follow-Up Studies; D006801:Humans; D007267:Injections; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000628:therapy*
keywords: coronary artery bypass; mesenchymal stromal cells; stem cell