title: Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.
abstract: BACKGROUND
  Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.
  
  
  RESULTS
  We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled ("dose optimization") study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled ("pivotal") study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.
  
  
  CONCLUSIONS
  Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Kristine
authors.initials: K
authors.lastname: Yee
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Malliaras
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America; Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, North Carolina, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Luthringer
authors.affiliation: Gift of Life Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Chak-Sum
authors.initials: CS
authors.lastname: Ho
authors.affiliation: National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.affiliation: National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Dawkins
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Supurna
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Doan Trang
authors.initials: DT
authors.lastname: Duong
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Seinfeld
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Middleton
authors.affiliation: Cedars-Sinai Biomedical Imaging Research Institute, Los Angeles, California, United States of America.
authors.forename: Rohan
authors.initials: R
authors.lastname: Dharmakumar
authors.affiliation: Cedars-Sinai Biomedical Imaging Research Institute, Los Angeles, California, United States of America.
authors.forename: Debiao
authors.initials: D
authors.lastname: Li
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America; Capricor, Beverly Hills, California, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America.
authors.forename: Raj R
authors.initials: RR
authors.lastname: Makkar
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, United States of America; Capricor, Beverly Hills, California, United States of America.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D009202:Cardiomyopathies / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D057785:Catheters; D002921:Cicatrix / Q000150:complications / Q000473:pathology*; D004106:Dilatation; D004699:Endocardium / Q000473:pathology*; D005260:Female; D007267:Injections; D008279:Magnetic Resonance Imaging; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D012038:Regeneration; D018874:Spheroids, Cellular / Q000166:cytology / Q000637:transplantation*; D016019:Survival Analysis; D034421:Sus scrofa; D014184:Transplantation, Homologous / Q000009:adverse effects