Abstract
Obstructive arterial disease is a major cause of morbidity and mortality in the developed world. Venous bypass graft surgery is one of the most frequently used revascularization strategies despite its considerable short and long time failure rate. Due to vessel wall remodeling, inflammation, intimal hyperplasia, and accelerated atherosclerosis, vein grafts may (ultimately) fail to revascularize tissues downstream to occlusive atherosclerotic lesions. In the past decades, little has changed in the prevention of vein graft failure (VGF) although new insights in the role of innate and adaptive immunity in VGF have emerged. In this review, we discuss the pathophysiological mechanisms underlying the development of VGF, emphasizing the role of immune response and associated factors related to VG remodeling and failure. Moreover, we discuss potential therapeutic options that can improve patency based on data from both preclinical studies and the latest clinical trials. This review contributes to the insights in the role of immunomodulation in vein graft failure in humans. We describe the effects of immune cells and related factors in early (thrombosis), intermediate (inward remodeling and intimal hyperplasia), and late (intimal hyperplasia and accelerated atherosclerosis) failure based on both preclinical (mouse) models and clinical data.
Highlights
The first saphenous vein graft (VG) implantation in humans was performed by Garrett et al in 1967, and together with the pioneering work of Favaloro et al, VG surgery became part of the standard revascularization strategies for patients with cor-Fabiana Baganha and Alwin de Jong shared first authorship Associate Editor Saskia de Jager oversaw the review of this articleAdaptation of VGs to their new arterial environment is characterized by structural vessel wall remodeling
Moderate intimal hyperplasia (IH) and adequate outward remodeling are necessary for proper arterialization and long-term graft patency
Despite the fact that some grafts stop remodeling after arterialization, other grafts progress to a clinical stenosis and may develop advanced atherosclerosis lesions
Summary
The first saphenous vein graft (VG) implantation in humans was performed by Garrett et al in 1967, and together with the pioneering work of Favaloro et al, VG surgery became part of the standard revascularization strategies for patients with cor-. EC activation and damage, e.g., after the distention of the vein during graft handling and surgery, resulted in an increase in L-selectin expression and adhesion of neutrophils to ECs [66]. Activation of NF-κB-mediated genes in the damaged vessel wall results in increased expression of pro-inflammatory cytokines, i.e., IL-1, MCP-1, TNFα, and TGF-β. Targeting TNFα to reduce VGF showed opposing effects involving IH, wall remodeling, and influx of immune cells depending on the activated TNFα receptor. Despite these initial promising results, the phase III PREVENT III and IV studies showed no differences in VGF prevention after CABG surgery between placebo and edifoligide group [96, 97] Another promising gene therapy is the adenoviral (Ad) delivery of TIMP-1, TIMP-2, or TIMP3 prior to grafting. This highlights that TEBVs may serve as arterial bypass grafts and represent a potential solution for future vascular surgery but still require optimization before large-scale clinical application is to be expected
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