Abstract 10211: Transient Ischemia Increases Transfection Efficiency of Intracoronary Ad5Luc in Pig Heart In Situ
Background: Efficiency of intracoronary adenoviral vector (Ad) uptake in the heart may be impaired by permeability barrier function of the vascular endothelium. Substances that increase vascular permeability (e.g.sodium nitroprusside, SNP) augment Ad transfection efficiency (TE). Ischemia-reperfusion (I/R) also increases vascular permeability, however it's effect on TE of Ad has not been determined.
Hypothesis: We tested the hypothesis that TE of Ad following intracoronary (IC) delivery is improved by I/R versus SNP in the pig heart in situ.
Methods: In 32 Yorkshire pigs (25 – 35 kg) an angioplasty balloon catheter was guided in the left anterior descending (LAD) coronary artery below the first diagonal branch. Protocol 1: Ischemia was induced by 75 min of balloon inflation. 15 min after start of reperfusion recombinant human Type 5 adenovirus (Ad5) encoding the luciferase marker gene (Ad5Luc,1011 viral particles/infusion) was infused into the LAD (Ad5Luc). A control group received IC vehicle infusion. The heart was harvested after 3 (n=4 each group) or 14 (n=8 each group) days of reperfusion. Protocol 2: Ad5Luc was delivered IC to non-ischemic LAD myocardium with (n=4) or without (n=4) co-administration of SNP (50 μg/min).
Results: The area at risk (AAR) and infarct size at 3 and 14 days after I/R were comparable between control and Ad5Luc groups. IC delivery of Ad5Luc into I/R myocardium caused no local inflammation (histology) or hemodynamic instability. Luciferase activity (LA) in Ad5Luc group was significantly (p<0.05) greater in the AAR compared to border zone and non-ischemic zone at both 3 (90.4±26.5, 9.6±6.1 and 0.2±0.6 pg Luc/g tissue, resp) and 14 days (18.4±10.1, 0.90.5 and 0.5±0.5 pg Luc/g tissue) of reperfusion; no LA was observed in controls. When Ad5Luc was delivered to non-ischemic myocardium in Protcol 2, LA was not observed in either group.
Conclusions: 1) IC Ad5Luc caused no hemodynamic abnormalities or inflammation; 2) Ad5 is taken up in I/R myocardium; and 3) no significant Ad5 is taken up in non-ischemic myocardium with or without SNP. The selective uptake of intracoronary Ad5 to I/R myocardium without any safety concerns validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients with myocardial ischemia.
- © 2010 by American Heart Association, Inc.