Abstract 3569: Optimal Timing of Transmyocardial Revascularization to Augment Stem Cell Transplantation
Background: We and others have reported that infarct pretreatment by transmyocardial revascularization (TMR) prior to transplantation of mesenchymal stem cells (MSC) enhances donor cell survival, angiogenesis and LV function. Determining the optimal interval between TMR and cell transplantation is critical to assess whether these sequential therapies have any clinical applicability. In this study, we sought to determine this optimal interval.
Methods: Female Lewis rats underwent LAD ligation 3 weeks before 10-channel needle TMR. After 15 minutes, 1 week or 2 weeks, 3 million male donor MSC were transplanted into the infarct. Two weeks later, donor cell survival was evaluated by realtime PCR for the sry gene, capillary and arteriolar densities by quantitative histology, regional perfusion by microspheres and LV function by echocardiography (N=8 for each outcome at each timepoint).
Results: TMR performed 15 minutes, 1 week and 2 weeks prior to MSC transplantation resulted in donor cell survival rates of 31±10%, 30±13% and 17±6% respectively (p<0.001 vs. 2 weeks). Total vascular densities in the scar were 12.2±3.7, 17.2±4.4 and 15.2±3.7 vessels per high power field respectively (p<0.05 vs. 15 min). Arteriolar densities did not differ between groups. Regional perfusion in the scar was greatest in the 1 week group (15 min, 84±26; 1 wk, 136±26; 2 wks, 92±16 microspheres/mg tissue, p<0.001 vs. 1 wk). Two weeks after MSC transplantation, LVEF was greatest in the 15 minute and 1 week groups (15 min, 74±2; 1 wk, 74±2; 2 wks, 64±4 % of baseline EF, p<0.001 vs. 2 wks).
Conclusions: TMR performed 15 minutes or 1 week prior to MSC transplantation results in optimal MSC survival and functional improvement, while angiogenesis and regional perfusion are maximized with a 1 week interval. A 2 week interval results in little synergism between these therapies. TMR and cell transplantation performed during the same procedure, whether surgically or percutaneously, may maximize functional recovery in an impaired ventricle. When maximal angiogenesis is required, a staged approach with TMR and CABG/PCI followed after 1 week by transendocardial cell delivery may be optimal. Cell harvesting and expansion must be timed so that adequate donor cells can be implanted within 1 week after TMR.