Intracoronary Cytoprotective Gene Therapy

• Published in: Journal of the American College of Cardiology Vol. 66; no. 2; pp. 139 - 153
• Main Authors: Woitek, Felix, MD, Zentilin, Lorena, PhD, Hoffman, Nicholas E., PhD, Powers, Jeffery C., BS, Ottiger, Isabel, BA, Parikh, Suraj, BS, Kulczycki, Anna M., BS, Hurst, Marykathryn, MS, Ring, Nadja, BS, Wang, Tao, MD, PhD, Shaikh, Farah, MD, Gross, Polina, BS, Singh, Harinder, PhD, Kolpakov, Mikhail A., MD, PhD, Linke, Axel, MD, Houser, Steven R., PhD, Rizzo, Victor, PhD, Sabri, Abdelkarim, PhD, Madesh, Muniswamy, PhD, Giacca, Mauro, MD, PhD, Recchia, Fabio A., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 14-07-2015; Elsevier Limited
• Subjects: Adenosine; Cardiology; Cardiomyocytes; Cardiomyopathy; Cardiovascular; Cardiovascular disease; Coronary vessels; Cytomegalovirus; Dogs; Enzymes; Experiments; Gene therapy; heart failure; Internal Medicine; Laboratory animals; Ligands; Statistical analysis; Studies; translational approach; Variance analysis; Vascular endothelial growth factor; Vectors (Biology); LV; vascular endothelial growth factor receptor-1; vascular endothelial growth factor receptor-2; GFP; LVEDP; cytomegalovirus; left ventricular; dilated cardiomyopathy; heart failure; VEGF; gene therapy; left ventricular end-diastolic pressure; CMV; green fluorescent protein; DCM; adeno-associated virus serotype 9; atrial natriuretic factor/protein; AAV; vascular endothelial growth factor; VEGFR-2; VEGFR-1; translational approach; ANF; nicotinamide adenine dinucleotide phosphate oxidase; HF; NOX2
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2015.04.071

Abstract 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.