title: Safety of intracoronary infusion of 20 million C-kit positive human cardiac stem cells in pigs.
abstract: BACKGROUND
  There is mounting interest in using c-kit positive human cardiac stem cells (c-kit(pos) hCSCs) to repair infarcted myocardium in patients with ischemic cardiomyopathy. A recent phase I clinical trial (SCIPIO) has shown that intracoronary infusion of 1 million hCSCs is safe. Higher doses of CSCs may provide superior reparative ability; however, it is unknown if doses >1 million cells are safe. To address this issue, we examined the effects of 20 million hCSCs in pigs.
  
  
  METHODS
  Right atrial appendage samples were obtained from patients undergoing cardiac surgery. The tissue was processed by an established protocol with eventual immunomagnetic sorting to obtain in vitro expanded hCSCs. A cumulative dose of 20 million cells was given intracoronarily to pigs without stop flow. Safety was assessed by measurement of serial biomarkers (cardiac: troponin I and CK-MB, renal: creatinine and BUN, and hepatic: AST, ALT, and alkaline phosphatase) and echocardiography pre- and post-infusion. hCSC retention 30 days after infusion was quantified by PCR for human genomic DNA. All personnel were blinded as to group assignment.
  
  
  RESULTS
  Compared with vehicle-treated controls (n=5), pigs that received 20 million hCSCs (n=9) showed no significant change in cardiac function or end organ damage (assessed by organ specific biomarkers) that could be attributed to hCSCs (P>0.05 in all cases). No hCSCs could be detected in left ventricular samples 30 days after infusion.
  
  
  CONCLUSIONS
  Intracoronary infusion of 20 million c-kit positive hCSCs in pigs (equivalent to ~40 million hCSCs in humans) does not cause acute cardiac injury, impairment of cardiac function, or liver and renal injury. These results have immediate translational value and lay the groundwork for using doses of CSCs >1 million in future clinical trials. Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Matthew C L
authors.initials: MC
authors.lastname: Keith
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Tokita
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Qian-Hong
authors.initials: QH
authors.lastname: Li
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Shahab
authors.initials: S
authors.lastname: Ghafghazi
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Moore Iv
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Brandon
authors.initials: B
authors.lastname: Elmore
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Alok
authors.initials: A
authors.lastname: Amraotkar
authors.affiliation: Department of Cardiothoracic Surgery, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Ganzel
authors.affiliation: Department of Cardiothoracic Surgery, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Kendra J
authors.initials: KJ
authors.lastname: Grubb
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Flaherty
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hunt
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Bathri
authors.initials: B
authors.lastname: Vajravelu
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D018189:Immunomagnetic Separation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013552:Swine
chemical_list: D019009:Proto-Oncogene Proteins c-kit