Abstract 3641: Consistent Improvement of Regional Perfusion and Function Following Selective Pressure-Regulated Retroinfusion of Ad HIF-1α/VP 16 in a Percutaneous Pig Model of Chronic Ischemia
A constitutively active adenoviral construct Ad2/HIF-1α/VP16 (Genzyme Corp.) is currently undergoing phase II clinical studies in limb ischemia using intramuscular delivery. Intramyocardial injections have been also the preferred delivery strategy for cardiac delivery despite marked heterogeneity of intramyocardial tissue distribution of HIF-1α expression. Catheter based selective pressure-regulated retroinfusion of the coronary vein results in more homogenous gene transfer and a more robust expression of target transgenes. Therefore, we performed a randomized investigator-blinded study comparing regional delivery with selective pressure-regulated venous retroinfusion of the heart in a percutaneous porcine model of chronic ischemia, using Ad2/HIF-1α/VP16. Pigs (n=7) were subjected to percutaneous implantation of a restrictor stent graft (Cx), leading to progressive stenosis and complete occlusion at day 28. Selective pressure-regulated retroinfusion was performed at day 28 for regional delivery of Ad2/HIF-1α/VP16, an empty virus and a saline buffer control. 28 days after treatment (day 56) the Ad2/HIF-1α/VP16 group showed statistically significant superiority to the control groups for the following parameters:
Capillary density (103±14 vs. 66±6 capillaries/field, p<0,001);
Collateral score (8±1 vs. 3±1, p<0,001);
Flow reserve with pacing (140/min) of regional myocardial blood flow (0,51±0,03 vs. 0,36±0,03 ml/g tissue, p=0,004);
Change in ejection fraction from day 28 to day 56 (ΔEF + 4,6 vs. −6,5, p<0,001);
LVEDP at day 56 (13±1 vs. 19±1 mmHg, p<0,001); and
Subendocardial segment shortening during pacing(150/min) (10 ± 2 % vs. 3±2 %, p<0,001).
Catheter-based regional myocardial gene transfer of Ad2/HIF-1α/VP16 targeted to the ischemic region by pressure-regulated selective cardiac vein retroinfusion significantly enhanced capillary density, collateral score and flow reserve with pacing. In addition, regional and global myocardial function improved substantially. These consistent findings suggest that a clinical phase I/II study using a regional, retrograde cardiac venous based approach in no-options patients with ischemic cardiomyopathy, may be warrented.