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Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial ‘delivery–efficacy’ mismatch

Gene Therapy volume 11, pages 1249–1255 (2004)Cite this article

Abstract

The aim of this study was to determine the effects of direct intramyocardial pVEGF165 gene transfer on regional myocardial blood flow in a porcine model of chronic myocardial ischaemia. Pigs underwent placement of an ameroid constrictor around the left circumflex coronary artery. After 3 weeks, animals received direct intramyocardial injections of pVEGF165 (20 × 50 μl at 1 μg/μl, n=11) or a plasmid vector encoding chloramphenicol acetyltransferase (20 × 50 μl at 1 μg/μl, n=11) into a specified target area (TA) of the left lateral wall. At 3 weeks after gene transfer, animals underwent final evaluation including a systematic assessment of regional myocardial blood flow (MBF) under resting and stress conditions. In all, 20 animals (10 per group) reached final studies. There was no change in mean arterial blood pressure or Rentrop collateral score from gene delivery to final studies in either group, nor were there differences between study groups. MBF was significantly higher in the areas adjacent to the TA in the VEGF group under resting (P<0.001) and stress conditions (P<0.05). In addition, pVEGF165 gene transfer abolished flow differences between the adjacent areas and the septum. MBF was not different between study groups in the TA, the anterior wall, or the septum. In conclusion, direct intramyocardial pVEGF165 gene transfer significantly improves myocardial blood flow. However, this effect is limited to the myocardial segments adjacent to the area of gene delivery. These data, therefore, demonstrate a spatial ‘delivery–efficacy’ mismatch with implications for myocardial gene delivery sites and detection of treatment effects in vivo.

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Acknowledgements

This work was supported by the British Heart Foundation (Grant No. 7704), the Royal Brompton Hospital Trust, Medicor Foundation (AHG), a Fellowship from the German Cardiac Society (PWR) and a Wellcome Trust Senior Clinical Fellowship (EWFWA). We gratefully acknowledge Dr Yoshikazu Yonemitsu and Dr Kazunori Nakagawa for the gift of the human VEGF165 cDNA, Dr Roger J Laham for valuable discussions, Professor Christof Huth, Dr Dirk Mahnkopf, Antje Mittag, and Uwe Rätzel for expert technical assistance during the studies, Robin Cassady for preparation of the plasmids and Tracy Higgins for her organisational support during the project.

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  1. P W Radke and A Heinl-Green: Both authors contributed equally to this study

Authors and Affiliations

  1. Department of Gene Therapy, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, UK

    P W Radke, U Griesenbach, S Ferrari, D M Geddes & E W F W Alton

  2. Klinik für Herz-Thorax-Gefässchirurgie, Universitätsklinik Magdeburg, Germany

    A Heinl-Green & O M Frass

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  1. P W Radke
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Radke, P., Heinl-Green, A., Frass, O. et al. Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial ‘delivery–efficacy’ mismatch. Gene Ther 11, 1249–1255 (2004). https://doi.org/10.1038/sj.gt.3302296

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