title: Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.
abstract: BACKGROUND
  While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed.
  
  
  OBJECTIVE
  To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect.
  
  
  METHODS
  A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute.
  
  
  METHODS
  Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI.
  
  
  METHODS
  The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size.
  
  
  RESULTS
  The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups.
  
  
  CONCLUSIONS
  Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00684021.
authors.affiliation: Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota, USA.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Traverse
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Henry
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: David X M
authors.initials: DX
authors.lastname: Zhao
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ellis
authors.forename: John R
authors.initials: JR
authors.lastname: Forder
authors.forename: R David
authors.initials: RD
authors.lastname: Anderson
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: Emerson C
authors.initials: EC
authors.lastname: Perin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chambers
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Baran
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raveendran
authors.forename: Charles
authors.initials: C
authors.lastname: Lambert
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Dejian
authors.initials: D
authors.lastname: Lai
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.forename: Doris A
authors.initials: DA
authors.lastname: Taylor
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
authors.forename: James D
authors.initials: JD
authors.lastname: Thomas
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Olson
authors.forename: Sherry
authors.initials: S
authors.lastname: Bowman
authors.forename: Judy
authors.initials: J
authors.lastname: Francescon
authors.forename: Carrie
authors.initials: C
authors.lastname: Geither
authors.forename: Eileen
authors.initials: E
authors.lastname: Handberg
authors.forename: Casey
authors.initials: C
authors.lastname: Kappenman
authors.forename: Lynette
authors.initials: L
authors.lastname: Westbrook
authors.forename: Linda B
authors.initials: LB
authors.lastname: Piller
authors.forename: Lara M
authors.initials: LM
authors.lastname: Simpson
authors.forename: Sarah
authors.initials: S
authors.lastname: Baraniuk
authors.forename: Catalin
authors.initials: C
authors.lastname: Loghin
authors.forename: David
authors.initials: D
authors.lastname: Aguilar
authors.forename: Sara
authors.initials: S
authors.lastname: Richman
authors.forename: Claudia
authors.initials: C
authors.lastname: Zierold
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Spoon
authors.forename: Judy
authors.initials: J
authors.lastname: Bettencourt
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Sayre
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Vojvodic
authors.forename: Sonia I
authors.initials: SI
authors.lastname: Skarlatos
authors.forename: David J
authors.initials: DJ
authors.lastname: Gordon
authors.forename: Ray F
authors.initials: RF
authors.lastname: Ebert
authors.forename: Minjung
authors.initials: M
authors.lastname: Kwak
authors.forename: Lemuel A
authors.initials: LA
authors.lastname: Moyé
authors.forename: Robert D
authors.initials: RD
authors.lastname: Simari
mesh_terms: D000368:Aged; D016026:Bone Marrow Transplantation / Q000379:methods*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000628:therapy*