Abstract 3723: AdvFGF-5 Gene Transfer to Swine with Ischemic Cardiomyopathy Increases Myocyte Number by Inhibiting Apoptosis and Promoting Myocytes to Re-enter the Cell Cycle
Background: Overexpressing fibroblast growth factor (AdvFGF-5) improves regional function without altering flow by increasing the number of myocytes in the cell cycle when ongoing apoptosis is absent. We performed the present study to determine whether the favorable effects of AdvFGF-5 on myocyte proliferation was maintained when ongoing apoptosis was present in a model associated with global LV dysfunction.
Methods: Swine instrumented with LAD and LCX stenoses to produce viable, dysfunctional myocardium (2-vessel stenoses) were studied in the closed-chest sedated state (propofol) 1-month after instrumentation. Responses before and 30 days after intracoronary administration of AdvFGF−5 (2 x 1012 vp, n=9) were compared to AdvEGFP (2 x 1012 vp, n=6). Histological analysis was performed to quantify myocyte size and myocyte nuclear density. The frequency of myocytes in the proliferative phase of the cell cycle and apoptosis were evaluated by the nuclear expression of Ki−67(clone MIB-1) and TUNEL staining.
Results: There was no significant infarction by TTC staining. LAD wall thickening and LV EF increased after AdvFGF−5 (27 ± 3 to 46 ± 6 %, 39±4 to 56±3 %, p<0.05 respectively). Histological analysis (Table⇓) demonstrated that AdvFGF−5 increased Ki−67 positive myocyte nuclei two-fold and decreased TUNEL positive myocytes six-fold. There was a corresponding reduction in myocyte cell diameter and a marked increase in myocyte nuclear density after AdvFGF−5 consistent with the regeneration of small cardiac myocytes.
Conclusion: These data indicate that AdvFGF-5 increases myocyte number by both stimulating myocytes to reenter the cell cycle as well as by decreasing myocyte apoptosis. Thus, AdvFGF-5 prevents deleterious LV remodeling by reversing the relation of myocyte cell survival and death indicating that it may be of great benefit as a therapeutic approach to prevent the progression of ischemic cardiomyopathy and heart failure.