Enhanced intimal thickening of expanded polytetrafluoroethylene grafts coated with fibrin or fibrin-releasing vascular endothelial growth factor in the pig carotid artery interposition model
Received 31 May 2006; received in revised form 24 August 2006; accepted 19 September 2006.
Objective
Intimal hyperplasia and surface thrombogenicity are major factors in the high failure rate of synthetic small-diameter bypass grafts. Vascular endothelial growth factor is a potent stimulus for endothelial growth, and its provision in a fibrin matrix coating at the luminal graft surface may hold a key to spontaneous graft endothelialization and improved graft patency.
Methods
Pigs underwent bilateral carotid artery interposition of expanded polytetrafluoroethylene grafts either impregnated with fibrin (n = 11)—engineered to locally release vascular endothelial growth factor121 (vascular endothelial growth factor–fibrin; n = 11)—or left uncoated (n = 12). Graft patency was assessed by quantitative carotid angiography followed by graft histomorphometry at the 1-month experimental end point.
Results
Patency rates were not significantly different between study groups. Grafts coated with fibrin or vascular endothelial growth factor–fibrin exhibited significantly increased angiographic narrowing at the proximal anastomosis (for both P < .05 vs uncoated) and no difference at the distal anastomosis and the grafts’ middle. Histological analysis showed 80% to 90% endothelial coverage and buildup of intima throughout the lengths of all grafts. Examination of the grafts’ midportion revealed significantly enlarged neointimal layers of smooth muscle actin-positive cells in grafts coated with vascular endothelial growth factor–fibrin (242 ± 47 μm2/μ) and fibrin (177 ± 41 μm2/μ), compared with uncoated grafts (131 ± 39 μm2/μ) (for both P < .05 vs uncoated). This thickening could not be explained by enhanced inflammation or vessel wall angiogenesis, which were minimal at the experimental end point.
Conclusions
Fibrin and vascular endothelial growth factor produced effects deleterious to graft healing, by increasing the narrowing at proximal anastomosis and neointimal growth beyond that seen in uncoated grafts. It may reflect direct activation by exogenous vascular endothelial growth factor of vascular smooth muscle cells.
aClinic of Cardiovascular Surgery, University of Geneva, Switzerland
bInstitute for Biomedical Engineering and Department of Materials Science, Swiss Federal Institute of Technology Zurich and University of Zurich, Switzerland
cDepartment of Clinical Pathology, University of Geneva, Switzerland
dDepartment of Anaesthesiology Research, University of Geneva, Switzerland
eDivision of Pediatric Cardiology, University Hospital of Geneva, Switzerland
fInstitute of Bioengineering, Swiss Federal Institute of Technology, Lausanne, Switzerland
gDepartment of Obstetrics, University Hospital of Zurich, Switzerland
hCenter for Integrative Human Physiology of the University of Zurich, Switzerland.
Address for reprints: Andreas Zisch, PhD, Department of Obstetrics, University Hospital Zurich, Frauenklinikstr. 10, 8091 Zurich, Switzerland
Beat H. Walpoth, MD, Clinic of Cardiovascular Surgery, University Hospital Geneva, 1211 Geneva 14, Switzerland
The study was supported by grants of the Swiss National Science Foundation and the Swiss Heart Foundation to B. H. W., the Gebert Ruef Foundation to A. H. Z. and J. A. H., and the European Union FP6-project Heart Repair.
⁎ Prisca Zammaretti and Mustafa Cikirikcioglu contributed equally to this article.
ABSTRACT