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European Heart Journal Advance Access published online on April 8, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi223
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European Heart Journal © The European Society of Cardiology 2005; all rights reserved
Received July 2, 2004
Revised January 25, 2005
Accepted February 17, 2005

Preclinical research

The efficacy of a ‘master switch gene’ HIF-1{alpha} in a porcine model of chronic myocardial ischaemia

Amanda Heinl-Green 1*, Peter W. Radke 1, Felix M. Munkonge 1, Oliver Frass 2, Jie Zhu 1, Karen Vincent 3, Duncan M. Geddes 1, and Eric W.F.W. Alton 1

1 Department of Gene Therapy, Faculty of Medicine, The National Heart and Lung Institute, Imperial College London, Manresa Road, London SW3 6LR, UK
2 Klink für Herz-Thorax-Gefasschirurgie, Universitatsklinik, Magdeburg, Germany
3 Genzyme Corporation, Framingham, MA, USA

* To whom correspondence should be addressed.
Amanda Heinl-Green, E-mail: a.heinl-green{at}ic.ac.uk


  Abstract

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{alpha}).

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{alpha} (Ad2/HIF-1{alpha} VP-16 1010 particles); (ii) plasmid DNA encoding HIF-1{alpha} (pHIF-1{alpha} NF{kappa}B 500 µg); (iii) pHIF-1{alpha} NF{kappa}B 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{alpha} 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{alpha} group was significantly different from the Ad2/control (P=0.03). No significant changes in any parameter were seen with plasmid HIF-1{alpha}. There were no differences in collateralization or capillary growth.

Conclusion Ad2/HIF-1{alpha} increased myocardial perfusion and improved LV function. Plasmid HIF-1{alpha} was not associated with improvements in any bioactivity endpoints.

Keywords: Angiogenesis; HIF-1{alpha}; Gene therapy; Myocardium.
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