The efficacy of a 'master switch gene' HIF-1alpha in a porcine model of chronic myocardial ischaemia.
OBJECTIVE
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-1alpha).


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-1alpha (Ad2/HIF-1alpha VP-16 10(10) particles); (ii) plasmid DNA encoding HIF-1alpha (pHIF-1alpha NFkappaB 500 microg); (iii) pHIF-1alpha NFkappaB 2500 microg; and (iv) adenoviral control (Ad2/CMV-empty vector 10(10) particles). Twenty injections (50 microL 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-1alpha 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-1alpha group was significantly different from the Ad2/control (P=0.03). No significant changes in any parameter were seen with plasmid HIF-1alpha. There were no differences in collateralization or capillary growth.


CONCLUSIONS
Ad2/HIF-1alpha increased myocardial perfusion and improved LV function. Plasmid HIF-1alpha was not associated with improvements in any bioactivity endpoints.
Heinl-Green
Amanda
A
Department of Gene Therapy, Faculty of Medicine, The National Heart and Lung Institute, Imperial College London, Manresa Road, London SW3 6LR, UK. a.heinl-green@ic.ac.uk
Radke
Peter W
PW
Munkonge
Felix M
FM
Frass
Oliver
O
Zhu
Jie
J
Vincent
Karen
K
Geddes
Duncan M
DM
Alton
Eric W F W
EW
D000818:Animals; D002908:Chronic Disease; D003326:Coronary Circulation / Q000502:physiology; D004452:Echocardiography; D018014:Gene Transfer Techniques; D005812:Genes, Switch; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011897:Random Allocation; D013552:Swine; D014157:Transcription Factors / Q000235:genetics*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors