Jussi Nurro1, Paavo J Halonen1, Antti Kuivanen1, Miikka Tarkia2, Antti Saraste3, Krista Honkonen1, Johanna Lähteenvuo1, Tuomas T Rissanen4, Juhani Knuuti3, Seppo Ylä-Herttuala5. 1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland. 2. Turku PET Centre, Turku University Hospital, Turku, Finland Department of Pharmacology, University of Helsinki, Helsinki, Finland. 3. Turku PET Centre, Turku University Hospital, Turku, Finland. 4. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland Department of Internal Medicine, Central Hospital of North Karelia, Joensuu, Finland. 5. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland Science Service Center, Kuopio University Hospital, Kuopio, Finland Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
Abstract
OBJECTIVE: Coronary heart disease remains a significant clinical problem, and new therapies are needed especially for patients with refractory angina for whom the current therapies do not provide sufficient relief. The aim of this study was to find out if angiogenic gene therapy using new members of the vascular endothelial growth factor (VEGF) family, VEGF-B186 and VEGF-DΔNΔC, increase myocardial perfusion as measured by the positron emission tomography (PET) 15O-imaging, and whether there would be coronary steal effect to the contralateral side. Furthermore, safety of intramyocardial angiogenic adenoviral gene transfer was evaluated. METHODS: Intramyocardial adenoviral (Ad) VEGF-B186 or AdVEGF-DΔNΔC gene transfers were given endovascularly into the porcine posterolateral wall of the left ventricle (n=34). Six days later, PET 15O-imaging for myocardial perfusion and coronary angiography were performed. RESULTS: AdVEGF-B186 and AdVEGF-DΔNΔC induced angiogenesis and increased total microvascular area 1.8-fold (95% CI 0.2 to 3.5) and 2.8-fold (95% CI 1.4 to 4.3), respectively. At rest, perfusion was maintained at normal levels, but at stress, relative perfusion was increased 1.4-fold (95% CI 1.1 to 1.7) for AdVEGF-B186 and 1.3-fold (95% CI 1.0 to 1.7) for AdVEGF-DΔNΔC, without causing coronary steal effect in the control area. The therapy was well tolerated and did not lead to any significant changes in laboratory safety parameters. CONCLUSIONS: Both AdVEGF-B186 and AdVEGF-DΔNΔC gene transfers induced efficient angiogenesis in the myocardium resulting in an increased myocardial perfusion measured by PET. Importantly, local perfusion increase did not induce any coronary steal effect. As such, both treatments seem suitable new candidates for the induction of therapeutic angiogenesis for the treatment of refractory angina. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE:Coronary heart disease remains a significant clinical problem, and new therapies are needed especially for patients with refractory angina for whom the current therapies do not provide sufficient relief. The aim of this study was to find out if angiogenic gene therapy using new members of the vascular endothelial growth factor (VEGF) family, VEGF-B186 and VEGF-DΔNΔC, increase myocardial perfusion as measured by the positron emission tomography (PET) 15O-imaging, and whether there would be coronary steal effect to the contralateral side. Furthermore, safety of intramyocardial angiogenic adenoviral gene transfer was evaluated. METHODS: Intramyocardial adenoviral (Ad) VEGF-B186 or AdVEGF-DΔNΔC gene transfers were given endovascularly into the porcine posterolateral wall of the left ventricle (n=34). Six days later, PET 15O-imaging for myocardial perfusion and coronary angiography were performed. RESULTS: AdVEGF-B186 and AdVEGF-DΔNΔC induced angiogenesis and increased total microvascular area 1.8-fold (95% CI 0.2 to 3.5) and 2.8-fold (95% CI 1.4 to 4.3), respectively. At rest, perfusion was maintained at normal levels, but at stress, relative perfusion was increased 1.4-fold (95% CI 1.1 to 1.7) for AdVEGF-B186 and 1.3-fold (95% CI 1.0 to 1.7) for AdVEGF-DΔNΔC, without causing coronary steal effect in the control area. The therapy was well tolerated and did not lead to any significant changes in laboratory safety parameters. CONCLUSIONS: Both AdVEGF-B186 and AdVEGF-DΔNΔC gene transfers induced efficient angiogenesis in the myocardium resulting in an increased myocardial perfusion measured by PET. Importantly, local perfusion increase did not induce any coronary steal effect. As such, both treatments seem suitable new candidates for the induction of therapeutic angiogenesis for the treatment of refractory angina. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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