Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B₁₆₇ in a Pre-Clinical Animal Model of Dilated Cardiomyopathy

Background Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. Objectives This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. Methods Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B₁₆₇ genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B₁₆₇ transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B₁₆₇ markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B₁₆₇ expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions. Conclusions Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B₁₆₇ gene transfer as an affordable and effective new therapy for nonischemic heart failure.