Recent findings in animals that stem cell therapy significantly reduces the development of LV dysfunction following MI (1
) have been rapidly translated into clinical trials using a variety of cell types including intra-coronary BMMNC administration (7
). Importantly, these trials have demonstrated that cell delivery following AMI is safe over several years of follow-up and meta-analyses review of these trials have found a small, but significant improvement in LV function (11
). However, despite these encouraging findings, many fundamental questions in cell therapy have not been addressed, including the important questions of optimal cell type, dose, and the timing of cell delivery post-AMI (16
). The CCTRN was formed to address many of these unresolved issues, and this is the first clinical cell therapy trial sufficiently powered to focus on the important question of timing of cell delivery post-AMI.
The timing of cell delivery following AMI is likely to be a critical factor in determining the efficacy of cell therapy due to the temporal changes that occur in the myocardium in the early days following AMI. These include the expression of growth factors and cytokines that may both promote cell survival and angiogenesis, or conversely, encourage myocyte apoptosis and adverse LV remodeling. Expression of chemokines, such as SDF-1 (13
) that may aid in stem cell homing, are up-regulated in the infarct zone in the first few days following AMI. This is consistent with recent findings in patients demonstrating the homing of radiolabelled progenitor cells to the infarct zone being greatest in the first few days following AMI (17
) where their secretion of vascular endothelial growth factor (VEGF) and insulin growth factor (IGF)-1 may improve perfusion and reduce apoptotic cell death in the infarct border zone (18
) Conversely, a strong inflammatory reaction and release of reactive oxygen species in the infarct zone may adversely affect survival of the injected cells. Additionally, there may be changes in the quality and quantity of harvested stem cells between the Day 3 and 7 time-point given the egress of cells from the bone marrow that occurs in this time window following AMI (19
). These factors among many, suggest that timing of stem cell administration post-AMI may be a critical component in dictating efficacy.
In the majority of published randomized clinical trials (7
), BMMNCs were administered between one and seven days post-AMI, but timing was not integrated into the randomization scheme. As a result, the designs of these trials were not sufficient to define the optimum timing of cell delivery following AMI. In a subgroup analysis, the REPAIR-AMI trial (7
) suggested that cell administration between 5 and 7 days was optimal in regards to recovery of LVEF. However, the ASTAMI trial (10
) administered BMMNCs in a similar time window and found no improvement in left-ventricular ejection fraction. However, this difference in outcomes may have also occurred due the different isolation procedure utilized in the ASTAMI trial (Lymphoprep) that may have resulted in reduced stem cell efficacy (20
The number of infused cells administered to patients post-AMI has varied significantly between the randomized trials, with differences up to several orders of magnitude (7
). Furthermore, the number of delivered cells within each trial has rarely been uniform, with some patients receiving up to three times the number of cells compared to other patients within the same trial. The failure to deliver a consistent cell dose remains a limitation of these trials. Only one published trial has attempted to address the issue of dose on its effects on LVEF (21
). In that trial, 44 patients were randomized to 10 versus 100 million BMMNCs administered 5 to 9 days post-AMI where a slightly greater improvement in LVEF was observed in the high-dose cohort (5% vs 3%). A recent meta-analysis found no effect between the number of cells infused and recovery of LVEF (11
). However, a second meta-analysis (12
) suggested that improvement in LVEF with BMMNC administration was dependent on the infusion of at least 100 million cells. Although the TIME trial is not a dose-ranging study, it will be the first major trial to administer the same number of cells to all of its patients (150 million), thus eliminating a potential variable that has not been controlled for in earlier trials.
The near exclusive use of autologous cells in cardiovascular cell therapy trials offers many important advantages from an immunologic and safety standpoint. However, recent research also suggests that the intrinsic efficacy of the cellular product may decline with age and important co-morbidities such as diabetes, etc. (22
) that are common to the population being studied. The CCTRN is committed to the systematic exploration of cell phenotypes by the establishment of a Biorepository that will perform migration assays, measure nitric oxide and cytokine production and characterize important receptor subtypes. In this randomized, Phase II, double-blind, controlled study, a well-defined and translatable cell product and dose will be utilized in a relatively high risk population. The timing of cell delivery will be addressed using time frames that are consistent with clinical applicability and an emerging safety profile. Additional human investigation in this and other clinical studies will provide a framework to complement ongoing basic science while further clarifying the therapeutic potential of cell delivery. Although this study is not designed to make head-to-head comparisons among cell types, it will generate a foundation for future studies to build upon within the CCTRN.