European Heart Journal Advance Access originally published online on April 8, 2005
European Heart Journal 2005 26(13):1327-1332; doi:10.1093/eurheartj/ehi223
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The efficacy of a ‘master switch gene’ HIF-1
in a porcine model of chronic myocardial ischaemia
1Department of Gene Therapy, Faculty of Medicine, The National Heart and Lung Institute, Imperial College London, Manresa Road, London SW3 6LR, UK
2Klink für Herz-Thorax-Gefasschirurgie, Universitatsklinik, Magdeburg, Germany
3Genzyme Corporation, Framingham, MA, USA
Received 2 July 2004; revised 25 January 2005; accepted 17 February 2005; online publish-ahead-of-print 8 April 2005.
* Corresponding author. Tel: +44 207 351 8339; fax: +44 207 351 8340. E-mail address: a.heinl-green{at}ic.ac.uk
Aims Therapeutic angiogenesis is a potential new treatment for patients unsuitable for conventional revascularization strategies. We investigated angiogenesis via a ‘master switch gene’ hypoxia inducible factor (HIF-1
).
Methods and results Ameroid occluders were placed around the left circumflex coronary artery of 74 pigs. Three weeks later, pigs were randomized to receive (i) adenovirus encoding HIF-1 (Ad2/HIF-1 VP-16 1010 particles); (ii) plasmid DNA encoding HIF-1 (pHIF-1 NF
B 500 µg); (iii) pHIF-1 NFB 2500 µg; and (iv) adenoviral control (Ad2/CMV-empty vector 1010 particles). Twenty injections (50 µL each) were administered epicardially via re-thoracotomy. Three weeks after gene delivery significant (ANOVA P=0.02) changes in myocardial perfusion during stress were seen in the area adjacent to injections. Post hoc testing (Bonferroni) demonstrated that the AdHIF-1 group was significantly (P=0.02) different from the Ad2/control. There were also significant (ANOVA P=0.02) differences in resting left ventricular (LV) function. Post hoc (Bonferroni) showed that the AdHIF-1 group was significantly different from the Ad2/control (P=0.03). No significant changes in any parameter were seen with plasmid HIF-1. There were no differences in collateralization or capillary growth.
Conclusion Ad2/HIF-1 increased myocardial perfusion and improved LV function. Plasmid HIF-1 was not associated with improvements in any bioactivity endpoints.
Key Words: Angiogenesis • HIF-1 • Gene therapy • Myocardium
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