title: Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction.
abstract: BACKGROUND
  Intracoronary delivery of cardiosphere-derived cells (CDCs) has been demonstrated to be safe and effective in porcine and human chronic myocardial infarction. However, intracoronary delivery of CDCs after reperfusion in acute myocardial infarction has never been assessed in a clinically-relevant large animal model. We tested CDCs as adjunctive therapy to reperfusion in a porcine model of myocardial infarction.
  
  
  RESULTS
  First, escalating doses (5, 7.5, and 10 million cells) of allogeneic CDCs were administered intracoronary 30 minutes after reperfusion. Forty-eight hours later, left ventriculography was performed and animals euthanized to measure area at risk, infarct size (IS), and microvascular obstruction. Second, identical end points were measured in a pivotal study of minipigs (n=14) that received 8.5 to 9 million allogeneic CDCs, placebo solution, or sham. Multiple indicators of cardioprotection were observed with 7.5 and 10 million allogeneic CDCs, but not 5 million CDCs, relative to control. In the pivotal study, IS, microvascular obstruction, cardiomyocyte apoptosis, and adverse left ventricular remodeling were all smaller in the CDC group than in sham or placebo groups. In addition, serum troponin I level at 24 hours was lower after CDC infusion than that in the placebo or sham groups, consistent with the histologically-demonstrated reduction in IS.
  
  
  CONCLUSIONS
  Intracoronary delivery of allogeneic CDCs is safe, feasible, and effective in cardioprotection, reducing IS, preventing microvascular obstruction, and attenuating adverse acute remodeling. This novel cardioprotective effect, which we call cellular postconditioning, differs from previous strategies to reduce IS in that it works even when initiated with significant delay after reflow.
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Malliaras
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Kristine
authors.initials: K
authors.lastname: Yee
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: James F
authors.initials: JF
authors.lastname: Dawkins
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Geoffrey
authors.initials: G
authors.lastname: De Couto
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Smith
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Kreke
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Seinfeld
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Middleton
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Romain
authors.initials: R
authors.lastname: Gallet
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Luthringer
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Ileana
authors.initials: I
authors.lastname: Valle
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Supurna
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Raj R
authors.initials: RR
authors.lastname: Makkar
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.).
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: From the Cedars-Sinai Heart Institute, Los Angeles, CA (H.K., E.T., K.M., K.Y., J.F.D., G.D.C., R.R.S., J.S., R.C.M., R.G., D.L., S.C., R.R.M., L.M., E.M.); Capricor Inc, Los Angeles, CA (R.R.S., M.K., I.V., L.M.); Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (H.K., K.F.); Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh (K.C.); and Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh (K.C.). eduardo.marban@csmc.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D003331:Coronary Vessels; D004195:Disease Models, Animal; D006333:Heart Failure / Q000601:surgery; D007269:Injections, Intra-Arterial; D057775:Ischemic Postconditioning / Q000379:methods*; D009203:Myocardial Infarction / Q000150:complications / Q000628:therapy*; D015425:Myocardial Reperfusion; D033581:Stem Cell Transplantation / Q000379:methods*; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous; D020257:Ventricular Remodeling / Q000502:physiology
keywords: acute myocardial infarction; animal models; coronary interventions; ischemic postconditioning