TY - JOUR
T1 - Intracoronary Cytoprotective Gene Therapy
T2 - A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy
AU - Woitek, Felix
AU - Zentilin, Lorena
AU - Hoffman, Nicholas E.
AU - Powers, Jeffery C.
AU - Ottiger, Isabel
AU - Parikh, Suraj
AU - Kulczycki, Anna M.
AU - Hurst, Marykathryn
AU - Ring, Nadja
AU - Wang, Tao
AU - Shaikh, Farah
AU - Gross, Polina
AU - Singh, Harinder
AU - Kolpakov, Mikhail A.
AU - Linke, Axel
AU - Houser, Steven R.
AU - Rizzo, Victor
AU - Sabri, Abdelkarim
AU - Madesh, Muniswamy
AU - Giacca, Mauro
AU - Recchia, Fabio A.
N1 - Publisher Copyright:
© 2015 American College of Cardiology Foundation.
PY - 2015/7/14
Y1 - 2015/7/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jacc.2015.04.071
DO - 10.1016/j.jacc.2015.04.071
M3 - Article
C2 - 26160630
AN - SCOPUS:84943571489
SN - 0735-1097
VL - 66
SP - 139
EP - 153
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 2
M1 - 21362
ER -