Combination Therapy With Granulocyte-Colony Stimulating Factor And Antiapoptotic Soluble Fas Gene Delivery In Postinfarction Heart Failure

Beneficial effects of granulocyte colony-stimulating factor (G-CSF) have been established on postinfarction left ventricular (LV) remodeling and function, at least in animal models, possibly through myocardial regeneration, repair process acceleration, or direct cardioprotection. Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction (MI) also reportedly improved LV remodeling and dysfunction at the chronic stage. We examined the combined effect of treatment with G-CSF and soluble Fas (sFas, an inhibitor of Fas/Fas ligand interaction) gene therapy on postinfarction heart failure. On the 3rd day of MI, the mice were randomly assigned into 4 groups. Group 1 was the control (n=26). In Group 2 (G-CSF alone, n=27), G-CSF (100 microg/kg/day) was intraperitoneally injected for 5 days and in Group 3 (sFas alone, n=13), adenovirus encoding sFas (Ad.CAG-sFas, 1 × 10 9 pfu/mouse) was injected into the himdlimb muscles. In Group 4 (combination, n=26), both G-CSF and Ad.CAG-sFas were given. According to echocardiography and cardiac catheterization, Group 4 was found to be best in survival rate and in alleviating post-infarction LV remodeling and dysfunction and Groups 2 and 3 were the second best as shown in the Table. Thus, an efficacy was evident of the combined regenerative cytokine and anti-apoptosis therapies during the subacute stage of MI for LV remodeling and heart failure. This novel therapeutic concept may be applied for management of patients with post-infarction heart failure who missed the chance for coronary recannalization at the acute stage. In Table, values, mean ± SEM; LVDd, LV end-diastolic diameter; %FS, %fractional shortening. P # ).