Abstract
In an open-chest model of acute infarct, epicardial delivery of hepatocyte growth factor (pCK-HGF-X7) gene improved left ventricle (LV) function. This study was designed to test (a) the efficacy of HGF gene in infarct scar delivered under magnetic resonance (MR) guidance and (b) the potential of multiple MR sequences in assessing the effects of pCK-HGF-X7 (treatment) and pCK-LacZ (control) genes on myocardial structure and function. Swine (six per group) were subjected to myocardial infarct, under X-ray fluoroscopy, and developed LV remodeling at 5 weeks. Multiple clinical magnetic resonance (MR) imaging sequences were performed before delivery of gene (at 5 weeks after infarction) and 5 weeks after delivery of gene. Under MR guidance, the active endovascular catheter was introduced into LV to transendocardially deliver 3.96 × 10(11) viral copies of pCK-HGF-X7 or pCK-LacZ in the border and core of the infarct scar. Histological evaluation of the infarct scar was performed 5 weeks after delivery of gene. At 5 weeks after infarction, there was no significant difference in measured cardiovascular MR parameters between the groups. The pCK-HGF-X7 gene caused significant improvement in the following parameters (P<.05 for these parameters): three-dimensional (3D) strain (radial, circumferential, and longitudinal) and perfusion (maximum upslope, peak signal intensity, and time to peak) compared with control pCK-LacZ at 5 weeks after delivery of the genes. The ejection fraction was higher in pCK-HGF-X7-treated (43 ± 1%) than in pCK-LacZ control (37 ± 1%, P<.05) animals. These changes are associated with a decrease in infarct scar size (11.3 ± 2.0% in pCK-LacZ control and 6.7 ± 1.3% in pCK-HGF-X7-treated animals, P<.01) and infarct transmurality in four out of five infarct scar segments (P<.05) on delayed contrast-enhanced MR imaging. Microscopic study confirmed the increase in capillary (P<.05) and arteriole (P<.05) density of infarct scar in pCK-HGF-X7-treated animals compared with pCK-LacZ control animals. Hepatocyte growth factor gene (pCK-HGF-X7) delivered under MR guidance into infarct scar ameliorated global function and 3D strain, increased regional perfusion and infarct resorption, and enhanced angiogenesis/arteriogenesis. This feasibility study provides novel approach and analysis methods and instrumentation for delivering and evaluating new locally delivered therapies.
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