Abstract 1328: Functional Relevant Angiogenic Switch in Hibernating Myocardium after eNOS Overexpression: a Preclinical Pig Study
Recently, we demonstrated the feasibility of liposomal eNOS cDNA transfection via retroinfusion in a model of acute myocardial ischemia/reperfusion. In the present study, we used this approach to target a phosphomimetic eNOS construct (eNOS S1177D) into chronic ischemic myocardium in a pig model of hibernation. We investigated whether eNOS S1177D overex-pression would affect neovascularization and function of the ischemic myocardium.
Methods: Pigs (n=6 per group) were subjected to percutaneous implantation of a reduction stent graft into the left anterior descending artery (LAD), inducing total occlusion within 28 days. At d28, 2 times 10min retroinfusion of saline solution containing liposomal GFP or eNOS S1177D cDNA (1.5mg/animal) was performed. Furthermore, L-NAME was applied orally from d28, where indicated. At d28 and d49, fluorescent microspheres were injected into the left atrium for perfusion analysis. Regional functional reserve (at atrial pacing 140/min) was assessed at d49 by subendocardial segment shortening (SES, sonomicrometry, % of RCx region). Endothelial cell proliferation (Ki67+ Pecam-1+ cells) and capillary density were assessed by immunohistochemistry, whereas collateral growth was analyzed by fluoroscopy.
Results: Endothelial NOS S1177D overexpression increased endothelial cell proliferation as well as capillary and collateral growth at d49. Concomitantly, eNOS S1177D overexpression enhanced regional myocardial perfusion from 54±4 (control) to 83±5% of Cx perfused myocardium, unless L-NAME was co-applied (69±5%). Similarly, eNOS S1177D cDNA improved functional reserve of the LAD (33±5 vs. 12±3% of Cx-perfused myocardium), except for L-NAME coapplication (13±6%).
Conclusion: Retroinfusion of eNOS S1177D cDNA induced neovasculariziation via endothelial cell proliferation, capillary and collateral growth. The resulting gain of perfusion partially resolves the functional impairment of hibernating myocardium in this preclinical model.