1. The NHLBI TIME Trial:
Role of Microvascular Obstruction in 2-Year Clinical and MRI Follow-up
Jay H. Traverse, MD
Principal Investigator, TIME Study
Minneapolis Heart Institute at Abbott Northwestern Hospital
University of Minnesota Medical School
Cardiovascular Cell Therapy Research Network (CCTRN)
2016 Scientific Sessions of the AHA
State no conflicts.

2. Rationale for TIME
Optimal timing for cell delivery post-AMI was not known and had not been directly tested in a prospective clinical trial.
Biochemical and structural changes in myocardium and bone marrow in the first week (cytokines, inflammation, ROS) may create optimal window for cell delivery.
Almost all BMC trials delivered cells ≤7 days post-AMI.
REPAIR-AMI subgroup suggested later delivery preferable to earlier
LateTIME showed no benefit when BMCs delivered 2-3 weeks post-MI.
BMCs in acute MI (cells vs. placebo)
TIME Study (118/120 patients completed) w/1 scheduled 11/10
Timing of intracoronary delivery (Day3 vs. Day7)
LateTIME Study (Completed – AHA 2011)
Timing of intracoronary delivery 2-3 weeks
BMCs in chronic ischemic LV dysfunction (cells vs. placebo)
FOCUS Study (Completed – results in 2012)
Intramyocardial delivery
Biorepository – U FL and U MN 2 2 2

3. TIME Study Design
Study Aim: assess the effect of autologous BMCs and timing of delivery at Day3 vs. Day7 post MI on measures of LV function
Target Population: 120 patients w/first anterior MI, reperfused by PCI + stent, with residual LV dysfunction (EF≤45%)
Treatment: 150 x 106 autologous BMCs or placebo (2:1) delivered by intracoronary infusion (Stop Flow)
Primary Endpoints: change in global and regional LV function
from baseline to 6 months by cardiac MRI
Secondary Endpoints: change in infarct size and LV volumes
Prespecified long-term (2-years) clinical and MRI F/U. 3 3

4. 6-month LVEF Results of TIME
Results for both infarct zone and border zone wall motion were also not significant by therapy group for 3 days, 7 days, or overall.

5. Two-Year Results of TIME
85 patients (BMC=58; Placebo=27) completed
stipulated 2-year clinical and MRI Follow-up.
- ICD implants (n=10)
- Death (n=3)
- Lost to Follow-up (n=7)
- MRI contraindications (n=15)

6. Change in LV Ejection Fraction
Placebo

7. Change in Infarct Size (g)

8. Change in LV End-Diastolic
Volume Index (ml / m2)

9. *MVO (late) measured 20-mins post-gadolinium
Prognostic Importance of MVO A B C * *
*MVO (late) measured 20-mins post-gadolinium
was identified in 47 /107 baseline (Day 3) MRIs
Figure 1. Infarct sizing and microvascular obstruction (MVO). Panel A: Short axis view with endo- and epicardial borders. Infarct (arrows) in the antero-, mid and infero-septal regions with microvascular obstruction (*) noted . Panel B: Quantification of infarct tissue based upon the intensity of the myocardium [minus the MVO(*)] using 5 standard deviations from the mean intensity to define infarcted myocardium, Panel C: Total infarct size including the MVO region

10. Baseline Data Stratified by MVO
MVO (n=47) No MVO (n=60) P-value
AGE
Female (n) / /
Infarct Size (g)
Peak CK (IU/ml)
LVEF (%)
LVEDVI (ml/m2)
LVESVI (ml/m2)

11. Effect of MVO on Changes in LVEF and
Volumes at 6-months
D LVEF

12. Change in LV Ejection Fraction

13. Change in Infarct Size (g)

14. Change in LVESVI (ml / m2)

15. Conclusions
Intracoronary delivery of autologous BMCs 3 or 7 days following STEMI did not improve LV function or attenuate LV remodeling at 6 months.
LV function, volumes and infarct size remain stable between 6 months and 2-years.
The presence of MVO is associated with significant reductions in the recovery of LV function, greater adverse LV remodeling and increased need for ICD implants. 15