AdVEGF-B186 and AdVEGF-DΔNΔC induce angiogenesis and increase perfusion in porcine myocardium.

Abstract

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-D^ΔNΔC, 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. Intramyocardial adenoviral (Ad) VEGF-B₁₈₆ or AdVEGF-D^ΔNΔC 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. AdVEGF-B₁₈₆ and AdVEGF-D^ΔNΔC 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-D^ΔNΔC, 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. Both AdVEGF-B₁₈₆ and AdVEGF-D^ΔNΔC 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.