aIndicates an order issued by the US Food and Drug Administration (FDA) to suspend an ongoing investigation; this hold was issued to ensure proper screening and monitoring of patients during the investigation by excluding those with left ventricular thrombus or atrial fibrillation who required anticoagulation therapy. bAll MRIs contraindicated because of implantable cardioverter-defibrillator placement.
BMC indicates bone marrow mononuclear cell; MI, myocardial infarction.
Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DXM, Ellis SG, Forder JR, Anderson RD, Hatzopoulos AK, Penn MS, Perin EC, Chambers J, Baran KW, Raveendran G, Lambert C, Lerman A, Simon DI, Vaughan DE, Lai D, Gee AP, Taylor DA, Cogle CR, Thomas JD, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Kappenman C, Westbrook L, Piller LB, Simpson LM, Baraniuk S, Loghin C, Aguilar D, Richman S, Zierold C, Spoon DB, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moyé LA, Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN) FT. Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial InfarctionThe TIME Randomized Trial. JAMA. 2012;308(22):2380-2389. doi:10.1001/jama.2012.28726
Author Affiliations: Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota (Drs Traverse and Henry and Ms Olson); School of Medicine, University of Minnesota, Minneapolis (Drs Traverse, Henry, Raveendran, and Zierold); College of Medicine, University of Florida, Gainesville (Drs Pepine, Forder, Anderson, Lambert, Cogle, and Handberg); Texas Heart Institute at St Luke's Episcopal Hospital, Houston (Drs Willerson, Perin, and Taylor, Mr Kappenman, and Ms Westbrook); School of Medicine, Vanderbilt University, Nashville, Tennessee (Drs Zhao and Hatzopoulos and Mss Bowman and Francescon); Cleveland Clinic Foundation, Cleveland, Ohio (Drs Ellis and Thomas and Ms Geither); Northeast Ohio Medical University, Rootstown (Dr Penn); Metropolitan Heart and Vascular Institute, Mercy Hospital, Minneapolis, Minnesota (Dr Chambers); St Paul Heart Clinic, United Hospital, St Paul, Minnesota (Dr Baran); Florida Hospital Pepin Heart Institute, Tampa (Dr Lambert); Mayo Clinic, Rochester, Minnesota (Drs Lerman, Spoon, and Simari); University Hospitals Case Medical Center, Cleveland, Ohio (Dr Simon); Feinberg School of Medicine, Northwestern University, Chicago, Illinois (Dr Vaughan); School of Public Health (Drs Lai, Piller, Simpson, Baraniuk, and Moyé and Mss Bettencourt, Sayre, and Vojvodic) and Medical School (Dr Loghin), University of Texas, Houston; Baylor College of Medicine, Houston, Texas (Drs Gee and Aguilar and Ms Richman); and National Heart, Lung, and Blood Institute (Drs Skarlatos, Gordon, Ebert, and Kwak).
Context 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.
Objectives 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.
Design, Setting, and Patients 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.
Interventions 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.
Main Outcome Measures 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.
Conclusion 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.
Trial Registration clinicaltrials.gov Identifier: NCT00684021
Cell therapy may eventually become a therapeutic option for patients after acute myocardial infarction (AMI), potentially preventing the transition to end-stage heart failure for which cardiac transplantation is currently the only curative procedure available. Recent meta-analyses of bone marrow mononuclear cell (BMC) delivery to the infarct zone after AMI have shown small improvements in left ventricular function after successful reperfusion.1 However, despite a growing number of trials, many fundamental questions such as optimal timing of BMC delivery remain unanswered.
Myocardium and bone marrow undergo important changes in the days to weeks after AMI that may affect stem or progenitor cell engraftment and survival.2 This notion has support from the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial,3 which determined in a prospectively specified analysis that delivery of BMCs 5 to 7 days after AMI resulted in greater improvement in left ventricular ejection fraction (LVEF) compared with earlier delivery. However, this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery.
The National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Research Network to address mechanistic questions in cardiovascular cell therapy. The recently completed LateTIME4 trial found BMC administration did not influence the ongoing postreperfusion recovery of either global or regional left ventricular function when delivered 2 to 3 weeks after AMI. Herein we present the results of a companion trial investigating the influences of the timing of cell delivery within the first week after AMI on the course of improving global and regional left ventricular function after reperfusion.
Timing In Myocardial infarction Evaluation (TIME) was a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial investigating the timing of intracoronary autologous BMCs within the first week after reperfusion in a high-risk cohort with ST-segment elevation myocardial infarction (STEMI).5 Between July 17, 2008, and November 15, 2011, 120 patients with LVEF of 45% or less by echocardiography after primary percutaneous coronary intervention (PCI) with stenting were enrolled. Exclusions included previous bypass surgery or prior STEMI with residual left ventricular dysfunction (LVEF <55%).
Each clinical center and the data coordinating center had independent institutional review board approval and oversight. Briefly, all qualifying participants provided written informed consent and were randomized on a 1 to 1 ratio to receive therapy on either day 3 or day 7 after primary PCI with stenting.
Race/ethnicity was self-described by participants. Demographic and clinical variables were determined by interview and by review of the patient's medical record. All patients had cardiac magnetic resonance imaging (MRI) at day 3 (baseline), and those randomized to delivery on day 7 had another MRI on day 7 (baseline). Patients underwent bone marrow aspiration on the morning of their treatment day, and BMCs were isolated using a closed, automated Ficoll cell processing system (Sepax, Biosafe)6 to ensure a uniform cellular product across centers.
After the cell product passed stipulated lot release criteria, a second randomization to either BMCs (2:1) or cell-free placebo occurred. Patients randomized to BMCs received a product containing 150 × 106 total nucleated cells (70%-80% of BMCs). Patients randomized to placebo received a cell-free product of 5% albumin in normal saline with 100 μL of autologous blood added to match color and consistency of the BMCs.
Within 12 hours of aspiration, patients received an infusion of BMCs or placebo in the infarct-related artery (Maverick balloon catheter, Boston Scientific) in 6 aliquots (5 mL each) using the stop-flow technique.5 All patients received heparin during the procedure to achieve an activated clotting time of greater than 200 seconds and were treated with aspirin and 75 mg of clopidogrel in addition to other guideline-recommended post-MI medications.
Cardiac MRI of global and regional left ventricular function has been previously described.4,5 Imaging using protocols developed by the MRI Core Laboratory (University of Florida) were performed using 1.5 T scanners that had been certified before study initiation.
The primary end points were change in global (LVEF) and regional left ventricular function (infarct and border zone) by MRI between baseline and 6 months when administered within the first 7 days after PCI and whether these changes were dependent on day of administration (day 3 vs day 7). The secondary end points included major adverse cardiovascular events as well as effects on left ventricular volumes and infarct size. Subgroup analysis for age, sex, race, hypertension, diabetes, statins, drug-eluting stent vs bare metal stent, and LVEF was prespecified. The distribution of participants across therapy groups precluded diabetes and statin analyses.
The statistical methods used have been detailed previously.5 Briefly, global left ventricular function was assessed by MRI-derived LVEF, for which we assumed an effect size or a placebo-adjusted change (difference in the change over time in the BMC group minus the change in the placebo group) of δ = 5% and a common group standard deviation of the difference of LVEF over time as σLVEF (Δ) = 7 as derived from Wollert et al,7 Lunde et al,8 Schächinger et al,9 and Janssens et al.10
Regional left ventricular function measure was defined as the change in wall motion over time in the infarct zone and in the infarct border zone. The infarct zone was defined as the segments with the largest 2-signal intensity-enhancement measures with gadolinium (using a 17-segment model). The border zone was defined as those regions adjacent to the infarct zone in which the signal intensity enhancement measures were in the 10% to 75% range of transmurality. For each of these measures of regional left ventricular function, we assumed an effect size of δ = 6.7 mm and a common group standard deviation of σ LVEF (Δ) = 9.5.7 Sixty patients each were required in an assessment of the effects of therapy on day 3 and day 7. This yield of 120 patients produced greater than 90% power for an overall assessment of therapy combining the day 3 and day 7 groups, as well as for the effect of therapy on day 3 vs the effect on day 7.
The Fisher exact test was used for categorical variables, and the t test was used for continuous variables to assess the compatibility of baseline variables between groups. All hypothesis testing was 2-sided, and all effect sizes and their 95% confidence intervals were evaluated using the general linear model, adjusting for center and demographics. No adjustments for multiple comparisons were made in this phase 2 study. A P value of .05 was used to assess statistical significance. SAS version 9.2 (SAS Institute Inc) was used for the statistical analyses.
Between July 2008 and November 2011, a total of 3347 patients were screened with almost half excluded due to having a LVEF greater than 45% (Figure 1). There were no statistically significant differences between the BMC and placebo groups in baseline characteristics except for higher peak creatine kinase and troponin levels among patients in the BMC group randomized to day 7 therapy and lack of diabetes among patients in the placebo group randomized to day 7 placebo therapy (Table 1). The qualifying LVEF (protocol-specified by echocardiography) within 48 hours of PCI ranged from 36.1% to 37.8%.
The mean time from PCI to bone marrow aspiration and cell processing was 3.3 days in the day 3 group and 7.5 days in the day 7 group. All BMC aspirates underwent automated cell processing at each center using Sepax. No patients experienced complications associated with the bone marrow harvesting.
The median time from bone marrow aspiration to infusion was 8.3 hours in the BMC group (Table 1); all patients received approximately 150 million total nucleated cells. The mean viability of the final BMC product was 98.2% and contained 2.2% of CD34 cells and 1.1% of cells that were both CD34 and CD133 cells (Table 2). The cell product was devoid of significant red blood cell contamination, contained only minuscule amounts of heparin (estimated at 0.01 U/mL), and most participants were infused within 1 hour of completion of cell processing,11 thereby avoiding concerns recently expressed in the literature.12,13 In vitro and in vivo studies comparing the delivery of Sepax-derived BMCs with that of open Ficoll-selected BMCs demonstrated phenotypic equivalence and equal efficacy on hind limb recovery in a murine model of hind limb perfusion.
All patients received systemic heparin during treatment infusion (as in REPAIR-AMI and other trials using the stop-flow technique). No complications were associated with intracoronary infusion.
Despite a perceived high-risk cohort of patients with moderate to severe left ventricular dysfunction after large STEMIs, there were few clinical events (Table 3). One death occurred (due to subarachnoid hemorrhage) after randomization to the BMC group but before cell delivery was performed. Ten patients underwent repeat revascularization and 6 received implantable cardioverter-defibrillators. There was no significant difference between the relative incidences of events comparing the BMC and placebo groups.
Follow-up MRIs were not performed in 8 patients because 1 had died, 3 had implantable cardioverter-defibrillator placements, and 4 declined for miscellaneous reasons (discomfort, anxiety, scheduling, or travel issues) (Figure 1).
When both BMC groups (n = 75) were combined and compared with a combined placebo group (n = 37), LVEF in the BMC group increased from 45.2% (95% CI, 42.8% to 47.6%) at baseline to 48.3% (95% CI, 45.3% to 51.3%) at 6 months while the combined placebo group increased from 44.5% (95% CI, 41.0% to 48.0%) to 47.8% (95% CI, 43.4% to 55.2%). Overall, there was no significant change in the difference between the 2 groups (−0.1% [95% CI, −4.1% to 3.9%]; P = .96). There was no significant difference between the change in regional wall motion in the infarct zone (−0.9 mm [95% CI, −3.0 to 1.2 mm]; P = .41) and the change in border zone (−0.5 mm [95% CI, −3.9 to 2.9 mm]; P = .78) (Table 4 and Figure 2).
A total of 41 patients in the BMC group and 22 patients in the placebo group had paired MRI data at baseline and at 6 months that were available for an analysis of global and regional left ventricular function in the day 3 group. The LVEF in the BMC group on the day of treatment was 46.1% (95% CI, 42.7% to 49.5%) and increased to 49.6% (95% CI, 45.3% to 53.9%) at 6 months, while the placebo group increased from 41.6% (95% CI, 37.4% to 45.8%) to 45.9% (95% CI, 40.1% to 51.7%) at 6 months. There was no significant difference between the change in LVEF of the BMC group compared with the change in LVEF of the placebo group (−0.9% [95% CI, −6.6% to 4.9%]; P = .76).
Similarly, infarct zone wall motion in the BMC group on day 3 of treatment was 4.2 mm (95% CI, 2.6 to 5.8 mm) compared with 3.7 mm (95% CI, 1.9 to 5.5 mm) in the placebo group. The difference in the changes over 6 months in infarct zone wall motion between the 2 groups was not significant (−0.3 mm [95% CI, −3.3 to 2.7 mm]; P = .82). In the border zone, wall motion in the BMC group on day 3 of treatment was 16.7 mm (95% CI, 13.3 to 20.1 mm) vs 12.6 mm (95% CI, 8.0 to 17.2 mm) in the placebo group. The difference between the 6-month changes in both groups was not significant (−0.8 [95% CI, −5.6% to 4.0%]; P = .75).
A total of 34 patients in the BMC group and 15 patients in the placebo group had paired MRI data at baseline and 6 months available for analysis of global and regional left ventricular function in the day 7 group. Baseline LVEF measured on treatment day 7 was 44.0% (95% CI, 40.7% to 47.3%) in the BMC group and increased to 46.8% (95% CI, 42.7% to 50.9%) at 6 months vs baseline LVEF in the placebo group of 48.8% (95% CI, 43.3% to 54.3%) and increased to 50.4% (95% CI, 43.7% to 57.1%) with no overall change in differences between groups (1.1% [95% CI, −4.7% to 6.9%]; P = .70).
Regional wall motion in the infarct zone was 3.8 mm (95% CI, 2.5 to 5.1 mm) in the BMC group and 4.7 mm (95% CI, 3.3 to 6.1 mm) in the placebo group. Overall, there was no significant difference in changes in infarct wall motion from baseline to 6 months between the 2 groups (−1.6 mm [95% CI, −4.5 to 1.4 mm]; P = .30). Baseline border zone wall motion was 13.5 mm (95% CI, 10.9 to 16.1 mm) in the BMC group and 13.8 mm (95% CI, 8.9 to 18.7 mm) in the placebo group with no overall change in differences between the 2 groups over 6 months (−0.1 mm [95% CI, −5.1 to 4.8 mm]; P = .96).
For LVEF, the placebo-adjusted effect of BMC on day 3 was −0.9% (95% CI, −6.6% to 4.9%) and on day 7 was 1.1% (95% CI, −4.7% to 6.9%). The difference between the 2 groups was not significant (2.0% [95% CI, −6.3% to 10.2%]; P = .64). For infarct zone wall motion, the placebo-adjusted effect of BMC on day 3 was −0.3 mm (95% CI, −3.3 to 2.7 mm) and on day 7 was −1.6 mm (95% CI, −4.5 to 1.4 mm). This difference also was not significant (−1.2 mm [95% CI, −5.5 to 3.1 mm]; P = .57). For border zone wall motion, the placebo-adjusted effect of BMC on day 3 was −0.8 mm (95% CI, −5.6 to 4.0 mm) and on day 7 was −0.1 mm (95% CI, −5.1 to 4.8 mm). The difference between these was not significant (0.6 mm [95% CI, −6.3 to 7.6 mm]; P = .86).
Left ventricular end diastolic volume index increased by 11.7 mL/m2 (95% CI, 7.4 to 16.0 mL/m2) in the BMC group and by 10.9 mL/m2 (95% CI, 5.1 to 16.7 mL/m2) in the placebo group, which was not significantly different (change: 0.8 mL/m2 [95% CI, −6.6 to 8.2 mL/m2]; P = .83). Left ventricular end systolic volume index increased by 5.0 mL/m2 (95% CI, 1.4 to 8.6 mL/m2) in the BMC group and by 4.3 mL/m2 (95% CI, −0.5 to 9.1 mL/m2) in the placebo group (change: 0.7 mL/m2 [95% CI, −5.5 to 7.0 mL/m2]; P = .82). Infarct volumes uniformly decreased in both groups at both times but again, the differences between the BMC and placebo groups were not significant. Day of treatment did not influence the secondary end points. Models adjusting for center, age, diabetes, hypertension, hyperlipidemia, weight, infarct location, infarct size (peak creatine kinase level), and percentage of CD34 cells did not change the unadjusted results.
Several predetermined subgroup analyses were performed in the BMC group. In contrast to previous studies,14,15 there was no improvement in the recovery of left ventricular function among patients with more depressed LVEF at baseline (LVEF < 45% via MRI). No difference was observed in global or regional function in patients stratified by ischemic time.
To our knowledge, TIME is the first cardiovascular cell therapy trial that was specifically designed to determine whether the timing of BMC administration after primary PCI influences left ventricular functional recovery. There was no overall effect of BMC treatment on this ongoing improvement at 6 months vs placebo despite previous supportive clinical data.1,3 Additionally, the day of cell delivery did not demonstrate an effect on the recovery of left ventricular function or on left ventricular volumes or infarct size.
The design of TIME was based on previous data that the timing of cell delivery may be critical.1,3,5 During the initial days to weeks after STEMI, there are significant temporal changes in the release of cytokines, such as stromal-derived factor 1,16 and growth factors such as vascular endothelial growth factor and insulin-like growth factor 1, that may support stem cell homing and angiogenesis leading to improved cell survival and engraftment.
Conversely, reactive oxygen species and inflammatory cytokines such as interleukin 1 and tumor necrosis factor released by myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival. These inflammatory mediators may impair the quality of cells harvested from the bone marrow as observed in a recent preclinical study demonstrating that BMCs are more potent several weeks after STEMI compared with those harvested a few days after STEMI as a result of inflammatory changes in the bone marrow mediated by interleukin 1.17 The relative role of these potential positive and negative influences on cell therapy is uncertain.
TIME was developed shortly after early randomized trials suggested that autologous, intracoronary BMCs may improve left ventricular function after AMI.7,9 Although several subsequent trials did not observe improved left ventricular function,8,10,18,19 a Cochrane meta-analysis suggested small improvement in LVEF (mean change, 1.8% [95% CI, 0.3% to 3.3%) when measured by MRI as used in TIME.1 A study to detect such a difference in LVEF would require 875 patients and would imply that this difference is biologically important. While these findings do not exclude this suggested effect size (for overall effect: 95% CI, −4.1 to 3.9; for day 3 effect: 95% CI −6.6 to 4.9; and for day 7 effect: 95% CI, −4.7 to 6.9), it is reasonable to critically examine some possible contributing aspects so that future studies in this area may proceed from an enlightened position.
Going forward it is crucial to understand how well this cohort did with contemporary management. In the age of aggressive primary prevention and rapid and successful primary PCI, identifying patients with significant left ventricular dysfunction after a first MI is challenging. The centers screened 3347 patients (of which about half did not have moderate or severe left ventricular dysfunction) to identify 132 patients who were randomized.20 Among those qualifying with moderate or severe left ventricular dysfunction, ischemic time was remarkably brief (median, 3-4 hours), all received PCI with stenting, and guideline-based medications were highly used. This management was associated with recovery of left ventricular function, yielding an aggregate LVEF at 6 months exceeding 48%. As has been reported elsewhere, existing data indicate that LVEF would be expected to continue to increase at 18 and 36 months in half of the cohort and links with mortality are no longer apparent when LVEF exceeds 45%.21 Since initiation of TIME and LateTIME, the Cardiovascular Cell Therapy Research Network has observed only a single cardiovascular-related death (subarachnoid hemorrhage prior to receiving study product) among 207 patients with moderate to large anterior STEMIs.
However, there is likely considerable heterogeneity among the cohort and it would be of interest to identify a population at greatest risk that might benefit (eg, those at risk for LVEF <45% at 6 months). If prospective cohorts cannot be identified, then an alternative approach is to recruit patients who have already demonstrated incomplete recovery at later time points and/or to consider novel cell types.22 The development of novel and sensitive measures of left ventricular function to serve as surrogate end points continues to be a requirement in this field.
In addition, the phenotype and functionality of the BMC product in this population may be an issue. Bone marrow mononuclear cells from patients with ischemic cardiomyopathy have reduced colony-forming unit capacities and impaired migration to stromal-derived factor 1 and vascular endothelial growth factor that translate into reduced blood flow in the ischemic hind limb model.20 Endothelial progenitor cells from patients with coronary artery disease also have impaired CXCR4 signaling with diminished neovascularization.23 Cytokine production from BMCs is reduced compared with other bone marrow and adipose-derived cell types.24 These considerations suggest that an autologous cell product derived from patients with coronary artery disease (as in TIME) may have less regenerative capacity vs allogeneic products obtained from younger, healthy donors.25
Although the field of cell therapy in cardiovascular disease has potential for identifying beneficial treatments, our study is consistent with the possibility that BMCs are not effective at improving left ventricular function when delivered into the immediate post-STEMI myocardial environment. However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI. Recent and ongoing studies continue to assess the role of BMCs in other areas such as heart failure and critical limb ischemia.26
Overall, the delivery of BMCs at 3 or 7 days after a STEMI and primary PCI did not affect subsequent improvement in left ventricular function at 6 months compared with placebo. These data should inform the future development of cell therapies for STEMI.
Corresponding Author: Judy Bettencourt, MPH, University of Texas, 1200 Herman Pressler, Room W-838, Houston, TX 77030 (email@example.com).
Published Online: November 6, 2012. doi:10.1001/jama.2012.28726
Author Contributions: Dr Moyé had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Traverse, Henry, Willerson, Ellis, Forder, Hatzopoulos, Penn, Raveendran, Vaughan, Lai, Piller, Simpson, Loghin, Aguilar, Bettencourt, Skarlatos, Gordon, Kwak, Moyé, Simari.
Acquisition of data: Traverse, Henry, Pepine, Willerson, Zhao, Ellis, Forder, Anderson, Penn, Perin, Chambers, Raveendran, Lambert, Lerman, Simon, Gee, Taylor, Cogle, Olson, Bowman, Francescon, Geither, Handberg, Kappenman, Westbrook, Piller, Simpson, Zierold, Sayre, Vojvodic, Moyé.
Analysis and interpretation of data: Traverse, Henry, Willerson, Zhao, Ellis, Forder, Anderson, Penn, Chambers, Raveendran, Vaughan, Lai, Gee, Taylor, Thomas, Baraniuk, Richman, Zierold, Bettencourt, Gordon, Ebert, Kwak, Moyé, Simari.
Drafting of the manuscript: Traverse, Henry, Willerson, Hatzopoulos, Penn, Perin, Gee, Geither, Kappenman, Simpson, Moyé, Simari.
Critical revision of the manuscript for important intellectual content: Traverse, Henry, Pepine, Willerson, Zhao, Ellis, Forder, Anderson, Penn, Perin, Chambers, Baran, Raveendran, Lambert, Lerman, Simon, Vaughn, Lai, Taylor, Cogle, Thomas, Olson, Bowman, Francescon, Handberg, Westbrook, Piller, Baraniuk, Loghin, Aguilar, Richman, Zierold, Spoon, Bettencourt, Sayre, Vojvodic, Skarlatos, Gordon, Ebert, Kwak, Moyé, Simari.
Statistical analysis: Traverse, Lai, Gee, Baraniuk, Kwak, Moyé.
Obtained funding: Traverse, Willerson, Hatzopoulos, Penn, Vaughan, Piller, Simpson, Simari.
Administrative, technical, or material support: Traverse, Pepine, Willerson, Forder, Anderson, Penn, Raveendran, Lambert, Lerman, Gee, Taylor, Thomas, Olson, Bowman, Francescon, Geither, Handberg, Westbrook, Piller, Simpson, Loghin, Aguilar, Bettencourt, Sayre, Vojvodic, Skarlatos, Gordon, Ebert, Simari.
Study supervision: Traverse, Ellis, Forder, Penn, Perin, Chambers, Raveendran, Lambert, Lerman, Simon, Thomas, Simpson, Kwak, Simari.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Henry reported serving as a consultant for Capricor; and receiving grant funding from Capricor and Osiris. Dr Pepine reported receiving funding for writing assistance, medicines, equipment, or administrative support from the National, Heart, Lung and Blood Institute (NHLBI) and Biosafe. Dr Willerson reported receiving funding from the NHLBI for participation in review activities. Dr Ellis reported receiving travel support from Abbott Vascular and Boston Scientific. Dr Hatzopoulos reported receiving funding from the NHLBI for writing and reviewing manuscripts, and participating in review activities. Dr Penn reported serving as a consultant to Aastrom and Juventas; receiving grant funding from Athersys; and having patents, receiving royalties, and owning stock/stock options in Juventas Therapeutics; and receiving reimbursement for travel expenses from Juventas Therapeutics. Dr Perin reported serving as a consultant to Cytori, Celgene, Biosense Webster, and Cephalon. Dr Simon reported serving as a consultant to Cordis/Johnson & Johnson, Medtronic Vascular, Merck, the Medicines Company, and Portola; serving as an expert witness for Cordis/Johnson & Johnson; and receiving payment for lectures from Abbott Vascular. Dr Taylor reported receiving payment for lectures from the American Heart Association. Dr Thomas reported that he served as president of the American Society of Echocardiography in 2011-2012; and received grant funding from the National Space Biomedical Research Institute/National Aeronautics and Space Administration. Dr Handberg reported receiving grant funding from Amorcyte, Baxter, and BDI Pharma. Ms Westbrook reported receiving travel reimbursement from Barnett International. All of the authors reported receiving research grant funding and support for travel expenses to meetings for the Cardiovascular Cell Therapy Research Network from the NHLBI.
Funding/Support: Funding for this trial was provided by the National Heart, Lung, and Blood Institute under cooperative agreement 5 U01 HL087318-04.
Role of the Sponsor: The funding sponsor had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation of this manuscript. The funding sponsor reviewed and approved the manuscript.
National, Heart, Lung and Blood Institute (NHLBI) Project Office Team: Sonia Skarlatos, PhD, David Gordon, MD, PhD, Ray Ebert, PhD, Wendy Taddei-Peters, PhD, Min Jung Kwak, PhD, and Beckie Chamberlin.
Cardiovascular Cell Therapy Research Network (CCTRN) Steering Committee Chair: Robert Simari, MD.
Timing In Myocardial infarction Evaluation (TIME) Trial Investigators and Clinical Teams:Minneapolis Heart Institute Foundation: Timothy Henry, MD, Jay Traverse, MD, David McKenna, MD, Beth Jorgenson, RN, and Rachel Olson, RN, MS. Cleveland Clinic Foundation: Stephen Ellis, MD, Marc Penn, MD, PhD, Saif Anwaruddin, MD, James Harvey, MD, Jane Reese Koc, MT, Carrie Geither, RN, Mark Jarosz, RN, and Cindy Oblak. Texas Heart Institute: James Willerson, MD, Emerson Perin, MD, PhD, Guilherme Silva, MD, James Chen, RN, Casey Kappenman, Deirdre Smith, RN, and Lynette Westbrook, RN, MS. University of Florida Department of Medicine: Carl Pepine, MD, Barry Byrne, MD, David Anderson, PhD, MD, John Wingard, MD, Eileen Handberg, PhD, Tempa Curry, RN, and Diann Fisk, MT. Vanderbilt University School of Medicine: David Zhao, MD, Antonis Hatzopoulos, PhD, Allen Naftilan, MD, Sherry Bowman, RN, Judy Francescon, RN, and Karen Prater. St Paul Heart Clinic, United Hospital: Ken Baran, MD, and Jody LaRock, RN. Metropolitan Heart and Vascular Institute, Mercy Hospital: Jeffrey Chambers, MD, and Betty Hargan, RN. University of Minnesota: Ganesh Raveendran, MD, Emily Caldwell, RN, and Barb Bruhn-Ding, RN. University Hospitals Case Medical Center: Daniel Simon, MD, Marco Costa, MD, and Stacey Mazzurco, RN. Florida Hospital Pepin Heart Institute: Charles Lambert, MD, PhD, and Elizabeth Szymanski, RN. Mayo Clinic: Amir Lerman, MD, and Kelly Noonan, RN. Michael E. DeBakey Medical Center: Biswajit Kar, MD.
Data Coordinating Center and Laboratory Teams:University of Texas School of Public Health: Lemuel Moyé, MD, PhD, Dejian Lai, PhD, Linda Piller, MD, MPH, Lara Simpson, PhD, Sarah Baraniuk, PhD, Shreela Sharma, PhD, Judy Bettencourt, MPH, Shelly Sayre, MPH, Rachel Vojvodic, MPH, Larry Cormier, Robert Brown, PhD, Diane Eady, Kristen Lucas, MS, Sibi Mathew, and Michelle Cohen, MPH. Baylor College of Medicine: Adrian Gee, PhD, Sara Richman, David Aguilar, MD. University of Texas Medical School: Catalin Loghin, MD. University of Florida Department of Medicine: John Forder, PhD (MRI Core Laboratory), Christopher R. Cogle, MD, and Elizabeth Wise (Biorepository Core-Florida). Cleveland Clinic C5 Research Imaging Core: James Thomas, MD, Allen Borowski, Annitta Flinn, and Cathy McDowell (Echo Core Laboratory). Center for Cardiovascular Repair: Doris Taylor, PhD, Claudia Zierold, PhD, and Marjorie Carlson (Biorepository Core-Minnesota).
Additional Contributions: The CCTRN acknowledges its industry partners Biosafe and Boston Scientific Corporation for contributions of equipment and technical support during the conduct of the trial. We thank the NHLBI gene and cell therapies data and safety monitoring board and the NHLBI protocol review committee for their review and guidance of the LateTIME trial.
This article was corrected for errors on December 28, 2012 and June 11, 2015.