Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up

Abstract

AimsWe evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DΔNΔC gene therapy in patients with refractory angina.Methods and resultsThirty patients were randomized to AdVEGF-DΔNΔC (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00 ± 0.36) at 3 months (1.31 ± 0.46, P = 0.045) and 12 months (1.44 ± 0.48, P = 0.009) whereas MPR in the reference area tended to decrease (2.05 ± 0.69, 1.76 ± 0.62, and 1.87 ± 0.69; baseline, 3 and 12 months, respectively, P = 0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months (1.26 ± 0.37, 1.57 ± 0.55, and 1.48 ± 0.48; respectively, P = 0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94 ± 0.32 and 1.76 ± 0.41 baseline and 12 months, respectively, P = 0.023).ConclusionAdVEGF-DΔNΔC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.

Therapeutic vascularization in regenerative medicine

“…However, because it has no heparin‐binding domain, it leads to a more diffuse distribution through ECM and induces more physiological vascular growth than VEGF‐A overexpression . Clinical trials of therapeutic angiogenesis by adenoviral delivery of VEGF‐D ΔNΔC are ongoing …”

“…81 Clinical trials of therapeutic angiogenesis by adenoviral delivery of VEGF-D ΔNΔC are ongoing. 82,83 The outcome of VEGF over-expression may also be significantly modified by promoting pericyte recruitment. Studies in skeletal muscle showed that the transition between normal and aberrant angiogenesis is not determined exclusively by VEGF dose, but rather by the balance between endothelial activation by VEGF and pericyte recruitment by PDGF-BB.…”

Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics

“…Furthermore, VEGF-mediated VEGFR-2 activation stimulates cardiomyocyte growth [33] and intramyocardially administrated VEGF-D facilitates therapeutic cardiac angiogenesis, increasing myocardial perfusion in patients with refractory angina [34]. Additionally, a meta-analysis showed that treatment with approved multiple tyrosine kinase inhibitors was associated with higher risk of congestive heart failure compared to non-tyrosine kinase treated [35].…”

Molecular Imaging to Monitor Left Ventricular Remodeling in Heart Failure

“…5). The value of imaging of αvβ3 integrin in predicting outcome of infarcted tissue after MI and demonstrating effects of therapies aimed at accelerating repair after MI, such as angiogenic gene therapy [117], still remains to be studied.…”