1. ¹Division of Cardiology, St Michael's Hospital, Toronto, Ontario, Canada
2. ²Victoria Heart Institute Foundation, Victoria, British Columbia, Canada
3. ³London Health Sciences Center, London, Ontario, Canada
4. ⁴Montreal Heart Institute Research Center, Montreal, Quebec, Canada
5. ⁵Notre-Dame Hospital, Montreal, Quebec, Canada
6. ⁶University of Alberta Hospital, Edmonton, Alberta, Canada
7. ⁷Royal Victoria Hospital, Montreal, Quebec, Canada
8. ⁸Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario, Canada
9. ⁹Foothills Hospital, Calgary, Alberta, Canada
10. ¹⁰Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada
11. ¹¹Cardiology PC, Birmingham, Alabama, USA
12. ¹²Arizona Heart Institute, Phoenix, AR, USA
13. ¹³Hopital Sacre-Coeur, Montreal, Quebec, Canada
14. ¹⁴Health Science Center, Winnipeg, Manitoba, Canada
15. ¹⁵Quebec Heart Institute, Quebec City, Quebec, Canada
16. ¹⁶Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada
17. ¹⁷GenVec Inc., Gaithersburg, MD, USA

Correspondence: Dr DJ Stewart, Division of Cardiology, St Michael's Hospital, 30 Bond Street, Room 6050 Queen Wing, Toronto, Ontario, Canada M5B 1W8. E-mail: stewartd@smh.toronto.on.ca

Received 12 January 2006; Revised 11 April 2006; Accepted 13 April 2006; Published online 22 June 2006.

Abstract

The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 10¹⁰ particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks 0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.