Abstract 2047: Combined Transmyocardial Revascularization and Cell-Based Gene Therapy Maximize Myocardial Repair After Infarction
Purpose: Transmyocardial revascularization (TMR), by laser or needle puncture, induces angiogenesis but cannot replace cells after infarction. Cell transplantation improves function in infarcted hearts but is limited by poor donor cell survival. We hypothesized that infarct pretreatment by TMR prior to transplantation of bone marrow cells (BMC) or BMC expressing angiogenic growth factors would have a synergistic effect on perfusion and function by increasing transplanted BMC survival and supplying cells required for myocardial repair.
Methods: Female Lewis rats underwent LAD ligation 3 weeks before 10-channel TMR with a 23g needle (3 groups), or no TMR (3 groups), followed after 15 minutes by transplantation of 3x106 male donor BMC, BMC transfected with VEGF, bFGF and IGF-1 (BMC+VBI), or medium alone (N=4 per group × 6 groups × 3 timepoints = 72 rats in total). At 1, 3 and 7 days, BMC survival was evaluated by realtime PCR for the Y chromosomal gene sry, vascular densities by quantitative histology, and LV function by echocardiography.
Results: Vascular densities did not differ between groups at 1 day. At 3 and 7 days, vascular densities were increased by BMC+VBI without TMR, and also by unmodified BMC with TMR (P<0.001), but were greatest in combined TMR and BMC+VBI (P<0.001) (at 4 weeks, vessels per 0.2 mm2 in the scar: medium alone 5.0±1.6, BMC 5.8±1.5, BMC±VBI 8.0±1.6, medium+TMR 6.0±1.6, BMC+TMR 8.4±3.4, BMC+VBI+TMR 11.6±1.3, P<0.001). BMC survival at 3 and 7 days was increased by TMR and also by overexpression of VEGF, bFGF and IGF-1 in the transplanted BMC (P<0.05). The combination of TMR and BMC+VBI resulted in the greatest cell survival (P<0.05) (% of BMC surviving at 7 days: BMC 24±4%, TMR and BMC 35±4%, BMC+VBI 41±8%, TMR and BMC+VBI 50±3%, P<0.05). After 7 days, LVEF was lowest in rats receiving neither BMC or TMR, and greatest in rats receiving both TMR and BMC+VBI (P=0.004).
Conclusion: The beneficial effects of cell-based gene therapy with VEGF, bFGF and IGF-1 on angiogenesis, transplanted cell survival and LVEF in infarcted rat hearts can all be significantly further enhanced by prior TMR. Combined pretreatment of the scar with TMR and cell-based gene therapy may maximize the efficacy of cell therapies for myocardial repair.