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

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.

• Authors: Felix Woitek, Lorena Zentilin, Nicholas E Hoffman, Jeffery C Powers, Isabel Ottiger, Suraj Parikh, Anna M Kulczycki, Marykathryn Hurst, Nadja Ring, Tao Wang, Farah Shaikh, Polina Gross, Harinder Singh, Mikhail A Kolpakov, Axel Linke, Steven R Houser, Victor Rizzo, Abdelkarim Sabri, Muniswamy Madesh, Mauro Giacca, Fabio A Recchia
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 66 Issue 2 Pg. 139-53 (Jul 14 2015) ISSN: 1558-3597 [Electronic] United States
• PMID: 26160630 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Vascular Endothelial Growth Factor B

Topics

• Animals
• Cardiomyopathy, Dilated (therapy)
• Coronary Vessels
• Disease Models, Animal
• Dogs
• Genetic Therapy (methods)
• Infusions, Intra-Arterial
• Male
• Transgenes
• Translational Research, Biomedical
• Treatment Outcome
• Vascular Endothelial Growth Factor B (genetics)