Abstract 11324: Intracoronary Gene Delivery of VEGF-B167, a Selective VEGFR-1 Agonist, Exerts Potent Therapeutic Effects in Dogs With Pacing-Induced Dilated Cardiomyopathy
Vascular endothelial growth factor-B (VEGF-B) activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGFR-1 receptors. Hypothetically, such properties render VEGF-B an ideal candidate for the therapy of dilated cardiomyopathy, a poorly treatable form of heart failure characterized by modest and widespread myocardial fibrosis and increased rate of apoptosis. We tested this hypothesis in chronically instrumented dogs with tachypacing-induced dilated cardiomyopathy. 1013 VEGF-B167 genes carried by adeno-associated-vectors type 9 (AAV9) were infused intracoronarily in 10 dogs at the beginning of the pacing protocol. Nine control pacing dogs were infused with AAV9-GFP. Although cell transduction was heterogeneous in myocardial layers (1 to 50%), after 4 weeks of LV pacing at 210 to 240 beats/min functional parameters were markedly preserved in VEGF-B- versus GFP-treated dogs, thus preventing the onset of decompensated failure: LV end-diastolic pressure was 12.1±4.6 vs 24.3±3.9 (congestive failure) mmHg, dP/dtmax 2112±665 vs 1481±508mmHg/sec, ejection fraction 47.1±4.6 vs 31.4±5.6% and LV circumferential systolic wall shortening 13.0±4.7 vs 6.7±3.1% (all P<0.05). We tested molecular mechanisms likely responsible for VEGF-B cardioprotective effects in cultured rat neonatal cardiomyocytes exposed to 10-8 M angiotensin II, a major pro-apoptotic factor in failing hearts. VEGF-B167, but not VEGF-A (dual VEGFR-1 and VEGFR-2 agonist) or VEGF-E (selective VEGFR-2 agonist), attenuated angiotensin-induced superoxide overproduction (Figure). This was consistent with the induction of mitochondrial superoxide dismutase overexpression and glutathione peroxidase-1. Our results, obtained with a standard method of interventional cardiology in a clinically-relevant animal model, support VEGF-B167 gene transfer as an affordable and highly effective new therapy for non-ischemic heart failure.
- © 2013 by American Heart Association, Inc.