Permanent coronary artery occlusion: cardiovascular MR imaging is platform for percutaneous transendocardial delivery and assessment of gene therapy in canine model.

Abstract

To provide evidence that vascular endothelial growth factor (VEGF) genes delivered transendocardially with magnetic resonance (MR) imaging guidance may neovascularize or improve vascular recruitment in occlusive infarction. All experimental procedures received approval from the institutional committee on animal research. Dogs with permanent coronary artery occlusion were imaged twice (3 days after occlusion for assessment of acute infarction; a mean of 50 days after occlusion +/- 3 [standard error of the mean] for assessment of chronic infarction). A mixture of plasmid VEGF and plasmid LacZ (n = 6, treated animals) or plasmid LacZ and sprodiamide (n = 6, placebo control animals) was delivered to four sites. MR fluoroscopy was used to target and monitor delivery of genes. The effectiveness of this delivery approach was determined by using MR imaging methods to assess perfusion, left ventricular (LV) function, myocardial viability, and infarct resorption. Histologic evaluation of neovascularization was then performed. MR fluoroscopic guidance of injectates was successful in both groups. Treated animals with chronic, but not those with acute, infarction showed the following differences compared with control animals: (a) steeper mean maximum upslope perfusion (200 sec(-1) +/- 32 vs 117 sec(-1) +/- 15, P = .02), (b) higher peak signal intensity (1667 arbitrary units +/- 100 vs 1132 arbitrary units +/- 80, P = .002), (c) increased ejection fraction (from 27.9% +/- 1.2 to 35.3% +/- 1.6, P = .001), (d) smaller infarction size (as a percentage of LV mass) at MR imaging (8.5% +/- 0.9 vs 11.3% +/- 0.9, P = .048) and triphenyltetrazolium chloride staining (9.4% +/- 1.5 vs 12.7% +/- 0.4, P = .05), and (e) higher vascular density (as number of vessels per square millimeter) at the border (430 +/- 117 vs 286 +/- 19, P = .0001) and core (307 +/- 112 vs 108 +/- 17, P = .0001). The validity of plasmid VEGF gene delivered with MR fluoroscopic guidance into occlusive infarction was confirmed by neovascularization associated with improved perfusion, LV function, and infarct resorption.