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Heng et al. Vessel Plus 2023;7:31 https://dx.doi.org/10.20517/2574-1209.2023.97 Page 3 of 14

by clinical symptoms is more prognostically important than vein graft stenosis alone. Since then, evolving
CABG practices, including the routine use of LIMA instead of SVG to the LAD, have significantly improved
survival after CABG. Indeed, in a contemporary study of 1,829 patients undergoing CABG by Lopes et al.,
93% of grafts to the LAD were LIMA, and there was no association between SVG failure and death;
however, there remained a significant association between SVG failure and the composite outcome of death,
[14]
myocardial infarction, or revascularization, driven mainly by revascularization .
PATHOGENESIS OF VEIN GRAFT FAILURE
SVG failure after CABG can manifest in either an early phase within one month of surgery, or in the
intermediate to late phase spanning up to several years after surgery. While early vein graft failure is often
attributed to technical aspects of surgery and resulting thrombosis, intermediate to late vein graft failure is
predominantly driven by neointimal hyperplasia leading to progressive vessel wall thickening followed by
superimposed atherosclerosis over time [Figure 1]. All SVGs are thought to be affected by neointimal
hyperplasia to some degree, owing to the biological cascade triggered by exposure of thin-walled veins to the
hemodynamic stresses of arterial circulation . The pathophysiologic mechanisms of neointimal
[6]
hyperplasia, therefore, serve as important therapeutic targets for the prevention of vein graft failure.

Proliferative phase
The proliferative phase of neointimal hyperplasia is characterized by rapid endothelial cell (EC) and smooth
muscle cell (SMC) proliferation in response to intimal injury. In native saphenous vein, the tunica intima
comprises a confluent monolayer of endothelium and is surrounded by a tunica media layer consisting of
[15]
an average of ten SMC layers . Vein harvesting and grafting during bypass surgery produces a denuded
area within the vessel wall of acute endothelium loss at anastomotic sites. Within the first 24 h after vein
graft transposition, EC proliferation commences in order to re-establish an endothelial monolayer covering
the denuded areas [16,17] . In rabbit models of jugular vein to carotid artery transposition, thymidine labeling
indices indicate that EC proliferation increases 400-fold during the first week after vein grafting. By 2 weeks,
denuded areas of vein grafts are completely reendothelialized, but EC proliferation continues at an
increased rate until 12 weeks after the initial injury [16,17] .

Concurrently, during the first 48 h after vein transposition, platelets and leukocytes also adhere to
denuded surfaces of vein grafts before the endothelial monolayer has been fully re-established. Platelet-
derived growth factor (PDGF), released by these platelets, is thought to promote early SMC proliferation
and migration into the intima. The peak activity of SMC proliferation occurs 1 week after surgery, and
returns to near quiescent levels 4 weeks after surgery, after which SMC mass remains relatively constant as
measured by morphometric analysis and DNA content. SMC thymidine labeling, however, can remain
slightly elevated for up to 24 weeks after surgery [16,17] .

Following the initial response of endothelial and intimal regeneration, the cell proliferation phase of
neointimal hyperplasia continues as a sustained process that extends over a considerable duration following
surgery. In porcine models of saphenous vein to carotid bypass surgery, immunohistochemistry for
proliferating cell nuclear antigen (PCNA) reveals heightened levels of cellular proliferation up to 6 months
after surgery, with PCNA-positive cells being found most abundantly in the tunica media, suggesting
broader involvement of multiple vessel layers in neointimal hyperplasia long-term [18,19] .

Secretory phase
After cell proliferation levels peak during the initial month following vein graft transposition, the secretory
phase of neointimal hyperplasia occurs, marked by increased production of extracellular matrix (ECM). The