title: Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.
abstract: BACKGROUND
  Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies.
  
  
  RESULTS
  Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDC-treated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy.
  
  
  CONCLUSIONS
  Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.
authors: Cedars-Sinai Heart Institute, Los Angeles, CA Department of Cardiology, Keio University School of Medicine, Shinjuku Tokyo, Japan.
authors: Hideaki
authors: H
authors: Kanazawa
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Eleni
authors: E
authors: Tseliou
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: James F
authors: JF
authors: Dawkins
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Geoffrey
authors: G
authors: De Couto
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Romain
authors: R
authors: Gallet
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Konstantinos
authors: K
authors: Malliaras
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Kristine
authors: K
authors: Yee
authors: Capricor Inc., Los Angeles, CA.
authors: Michelle
authors: M
authors: Kreke
authors: Capricor Inc., Los Angeles, CA.
authors: Ileana
authors: I
authors: Valle
authors: Cedars-Sinai Heart Institute, Los Angeles, CA Capricor Inc., Los Angeles, CA.
authors: Rachel R
authors: RR
authors: Smith
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Ryan C
authors: RC
authors: Middleton
authors: Gift of Life Michigan, Ann Arbor, MI.
authors: Chak-Sum
authors: CS
authors: Ho
authors: Cedars-Sinai Biomedical Imaging Research Institute, Los Angeles, CA.
authors: Rohan
authors: R
authors: Dharmakumar
authors: Cedars-Sinai Biomedical Imaging Research Institute, Los Angeles, CA.
authors: Debiao
authors: D
authors: Li
authors: Cedars-Sinai Heart Institute, Los Angeles, CA.
authors: Raj R
authors: RR
authors: Makkar
authors: Department of Cardiology, Keio University School of Medicine, Shinjuku Tokyo, Japan.
authors: Keiichi
authors: K
authors: Fukuda
authors: Cedars-Sinai Heart Institute, Los Angeles, CA Capricor Inc., Los Angeles, CA.
authors: Linda
authors: L
authors: Marbán
authors: Cedars-Sinai Heart Institute, Los Angeles, CA eduardo.marban@csmc.edu.
authors: Eduardo
authors: E
authors: Marbán
mesh_terms: D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008264:Macrophages / Q000473:pathology; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015425:Myocardial Reperfusion / Q000009:adverse effects; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000637:transplantation*; D013318:Stroke Volume; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014184:Transplantation, Homologous; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
keywords: allogeneic transplantation; cardioprotective effect; cardiosphere‐derived cells