Ischemia-Reperfusion Increases Transfection Efficiency of Intracoronary Adenovirus Type 5 in Pig Heart In Situ

Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia. Fluoroscopically guided angioplasty balloon catheters occluded the coronary artery in Yorkshire pigs and delivered adenoviral type 5 vector encoding the luciferase gene (Ad5Luc, 1011 viral particles). TE (luciferase activity) was minimal and was not augmented by IC co-administration of 50 μg/min sodium nitroprusside to nonischemic myocardium. Two (but not one) 3-min episodes of occlusion tended to increase luciferase activity (p=0.06), and luciferase activity was further increased by IC co-administration of nitroglycerin (p<0.001). After 75 min of coronary artery occlusion, luciferase activity was greater than with shorter periods of ischemia, and was significantly greater in the ischemia-reperfused zone compared to the border zone 3 and 14 days after infusion; there was no transfection in nonischemic myocardium. IC delivery of Ad5Luc into post-ischemic myocardium caused no local inflammation or hemodynamic instability. We conclude that the uptake of IC Ad5 to ischemic reperfused myocardium validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients following myocardial ischemia. Shi and colleagues evaluate whether the transfection efficiency of adenovirus type 5 vector following intracoronary infusion in Yorkshire pigs can be improved either by increasing vascular permeability with nitrates or by ischemia. Transgene activity increased with two 3-minute periods of ischemia as well as with co-administration of nitroglycerin. Longer ischemic periods that result in myocardial infarction led to significantly greater transfection activity in the ischemia-reperfused area, at both 3 and 14 days after infusion.