Abstract 419: Cytokine-Mediated Release of Vascular Endothelial Growth Factor and Stromal-Derived Factor 1 Induces Neovascularization and Prevents Left Ventricular Remodeling in a Porcine Model of Ischemia Reperfusion.
Cytokine therapy has been suggested to improve left ventricle (LV) function after myocardial infarction (MI). The mechanisms for this benefit remain debatable. We investigated the impact of a prolonged combined therapy with Darbepoetin alfa (DARB) and Granulocyte Colony-Stimulating Factor (G-CSF) on LV function and vascular density after MI, correlating it with circulating progenitor cells (CPC), Vascular Endothelial Growth Factor (VEGF) and Stromal-Derived Factor 1 (SDF-1) release.
Methods and Results: MI was induced in swine by a 90 minutes balloon occlusion of the left anterior descending artery. Animals were divided between treatment group with DARB-GCSF combination therapy (bolus of DARB 0.9 and GCSF 10ug/kg IV at time of reperfusion, followed by 5 doses of GCSF 5ug/kg SC from day 5 to 9, and four doses of 0.45ug/kg DARB SC once per week starting at day 1, n = 8) or control group (saline injections, n = 8). White blood cells (WBC), CPC, defined by CD45, CD31, CD90 and SLA-1 expression, and circulating levels of VEGF and SDF-1 were assessed at baseline (T0), 1 (T1), 2 (T2), and 3 (T3) weeks post-MI. LV function was assessed by echocardiography at T0, T1 and T6 (6 weeks post-MI), and vascular density by histology at T6. MI size was the same in both groups by post-MI CPK peak and LV ejection fraction (EF) at T1 (41+/−1 vs. 40+/−2%). In the treatment group only, from T0 to T1, there was an increase in WBC (16 ± 2 to 42 ± 2 x 106/ml, p <0.01) and CPC (5 ± 1 to 9 ± 1 x 105/ml, p = 0.01) and SDF-1 levels peaked from T0 to T2 (1345+/−60 to 1554 +/− 60 pg/ml; p<0.01) and stabilized at T3. All these values remained unchanged in the control group. VEGF levels (pg/ml) peaked at T2 in both groups (14+/−1 vs. 12+/−1), but remained increased at T3 in DARB-GCSF group only (13+/−1 vs. 9+/−1; p<0.01). LVEF (41+/−1 vs. 33+/−1, p<0.01) and arteriole density at the infarct zone (44+/−14 vs. 27+/−12/mm2, p = 0.02) and remote zone (18 +/−8 vs.11+/−5, p = 0.055) were higher compared to the control at T6.
Conclusion: Our data suggest that prolonged therapy with DARB-GCSF combination after MI modulates angiogenesis and promotes stabilization of LV function by increasing CPC, and releasing SDF-1 and VEGF. This therapy provides a novel strategy to prevent post-MI LV remodeling and potentially improve outcome.