title: Timing of bone marrow cell therapy is more important than repeated injections after myocardial infarction.
abstract: BACKGROUND
  Bone marrow cell treatment has been proposed as a therapy for myocardial infarction, but the optimal timing and number of injections remain unknown.
  
  
  METHODS
  Myocardial infarction was induced in mice followed by ultrasound-guided injection of mouse bone marrow cells at different time points post myocardial infarction (Days 3, 7, and 14) as monotherapy and at Days 3+7 as "double" therapy and at Days 3+7+14 as "triple" therapy. Controls received saline injections at Day 3 and Days 3+7+14. Left ventricular ejection fraction was evaluated post myocardial infarction prior to any therapy and at Day 28. Hearts were analyzed at Day 28 for infarct size and survival of donor cells.
  
  
  RESULTS
  Left ventricular ejection fraction decreased from 55.3±0.9% to 37.6±0.6% (P<.001) 2 days post myocardial infarction in all groups. Injection of bone marrow cells at Day 3 post myocardial infarction resulted in smaller infarct size (17.8±3.6% vs. 36.6±7.1%; P=.05) and improved LV function (left ventricular ejection fraction 40.3±2.0% vs. 31.1±8.3%; P<.05) compared to control. However, delayed therapy at Day 7 or 14 did not. Multiple injections of bone marrow cells, either double therapy or triple therapy, did not result in reduction in infarct size, but led to improvements in left ventricular ejection fraction at Day 28 compared to control (39.9±3.6% and 38.8±5.5% vs. 34.8±5.3%; all P<.05). The number of donor cells surviving at Day 28 did not correlate with improvement in left ventricular ejection fraction.
  
  
  CONCLUSIONS
  Injection of bone marrow cells at Day 3 reduced infarct size and improved left ventricular function. Multiple injections of bone marrow cells had no additive effect. Delaying cell therapy post myocardial infarction resulted in no functional benefit at all. These results will help inform future clinical trials.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Francisco, CA 94143-0103, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sievers
authors.forename: Megha
authors.initials: M
authors.lastname: Prasad
authors.forename: Rachel
authors.initials: R
authors.lastname: Mirsky
authors.forename: Henry
authors.initials: H
authors.lastname: Shih
authors.forename: Maelene L
authors.initials: ML
authors.lastname: Wong
authors.forename: Franca S
authors.initials: FS
authors.lastname: Angeli
authors.forename: Jianqin
authors.initials: J
authors.lastname: Ye
authors.forename: Junya
authors.initials: J
authors.lastname: Takagawa
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Springer
authors.forename: William
authors.initials: W
authors.lastname: Grossman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Boyle
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002470:Cell Survival; D004195:Disease Models, Animal; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins