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.
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PJH and AK contributed equally to this study.
Contributors JN designed the experiments, performed the animal experiments, laboratory analyses and the statistical analysis, cleaned and analysed the data, and drafted and revised the paper. He is the study guarantor. PJH and AK designed the experiments, performed the animal experiments and laboratory analyses, analysed the data, and drafted and revised the paper. PJH and AK provided equal contribution. MT designed and performed the PET experiments, interpreted and analysed PET data, and drafted and revised the paper. AS and JK designed the PET experiments, interpreted PET data, and drafted and revised the paper. KH and JL analysed the data, and drafted and revised the paper. TTR and SY-H designed the experiments, analysed the data and drafted and revised the paper.
Funding Academy of Finland, Helsinki; European Research Council Advanced grant, ADVance (EU grant agreement ref. 290002); the Sigrid Juselius Foundation, Helsinki; Finnish Cultural Foundation—North Savo Regional fund, Kuopio; Finnish Cultural Foundation, Helsinki; Maud Kuistila Foundation, Helsinki; Ida Montin Foundation, Helsinki; Finnish Foundation for Cardiovascular Research, Helsinki; Antti and Tyyne Soininen Foundation, Kuopio; The Finnish Medical Foundation, Helsinki; and Kuopio University Hospital, Kuopio.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.