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Objective: We hypothesized that angiogenic response and efficacy of angiopoietin-1(Ang-1) gene delivery in the infarcted myocardium would be influenced by the mode of delivery.
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Lei Ye1, Husnain Kh Haider2, ShuJia Jiang2, RuSan Tan3, Wee Chi Toh1, RuoWen Ge4, In Chin Song5, Peter K. Law6, Eugene KW Sim7.
1NUMI, National University of Singapore, Singapore, Singapore, 2Department of Pathology, University of Cincinnati, Cincinnati, OH, USA, 3Department of Cardiology, National Heart Center, Singapore, Singapore, 4Department of Biological Sciences, National University of Singapore, Singapore, Singapore, 5Department of Experimental Surgery, Singapore General Hospital, Singapore, Singapore, 6Cell Transplants Singapore Pte. Ltd, Singapore, Singapore, 7Surgery, Department of Surgery, National University of Singapore & Gleneagles JPMC Cardiac Center, Brunei Darussalam, Singapore, Singapore.
Methods: Ang-1 was packaged into adenoviral vector(Ad-Ang-1) and used for either direct injection or transduction of skeletal myoblasts(SkM). Experimental myocardial infarction model was developed in 20 female pigs by coronary artery ligation. Three weeks later, the animals were grouped to receive intramyocardial injection of 5 ml DMEM alone (group 1 n=6), or containing 1x1010 PFU Ad-Ang-1(group 2 n= 7), or 3x108 lac-z labeled SkM transduced with Ad-Ang-1(group 3 n=7). Animals were maintained on 5mg /kg cyclosporine for 6 weeks. The animals were euthanized at 6 and 12 weeks post respective treatment and their heart tissue was processed for histological studies.
Results: Extensive survival of the lac-z positive SkM was observed in pig heart up to 12 weeks after cell transplantation. Blood vessel density(x100) by fluorescent immunostaining for vWF-VIII and smooth muscle actin in group 3 increased from 42.25±3.82 and 34.73± 2.52 at 6 weeks to 46.57±1.76 and 41.36 ±1.53 at 12 weeks as compared to group 1(16.0±0.91; 7.88± 0.52; p<0.01) and group 2(30.63±2.11p<0.01; 37.5± 2.04) at 6 weeks and (13.44±0.9; 7.00± 0.58; p<0.01) of group 1 and (37.43±2.77; 35.86± 2.79) of group 2 at 12 weeks. Mature blood vessel index at was the highest in group 2 at 6 (98.5± 4.2%) and 12(96± 2.2%) weeks and followed by group 3(85.26± 2.86%; 91.64± 7.96%). These were significantly higher than those of group 1(49.20± 4.7%; 52.08± 5.9%). The mean blood vessel diameter in group 2 and 3 at 6 weeks were significantly smaller than those of group 1(11.72± 1.67 μm p<0.05). However, they increased to 10.9 ± 1.21 μm and 10.64± 1.14 μm at 12 weeks. Significantly improved blood flow was achieved by group 3 as compared with group 1 and group 2 at 6 weeks. Significantly improved ejection fraction was only achieved in group 3(49.22±5.92%, p=0.037) as compared with group 1 (36.84±3.02%).
Conclusions: SkM mediated Ang-1 delivery is associated with better improved regional perfusion and heart function as compared with direct Ad-Ang-1 administration for cardiac repair.
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