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

explored the use of oversized and non-restrictive stents. In a study by Izzat et al., they examined the
[18]
application of 5-, 6-, and 8-mm Dacron velour stents to saphenous veins in carotid interposition surgery .
At 4 weeks, all stented vein grafts demonstrated equal reductions in medial thickness, but only 6- and 8-mm
stented vein grafts showed significant reductions in neointimal thickness in contrast to 5-mm stented grafts
with comparatively greater intimal thicknesses. At odds with early stent designs advocating tight-fit and
diameter reduction of vein grafts, these data and subsequent work have proposed that oversized loose-fit
vein graft supports produce more effective suppression of intimal thickening [19,22,23] . Additionally, the
microporous nature of stent materials such as Dacron velour is thought to play a role, in contrast to
microporous PTFE used previously.

Neoadventitial formation
Apart from their influence on vessel intima and media, external vein graft stents have been shown to
produce cellular and chemotactic changes to the adventitial environment surrounding vein grafts which can
contribute to either favorable or unfavorable remodeling. In early studies of tight-fitting stents, rigid sheaths
surrounding vein grafts would produce a foreign body giant cell reaction and become enveloped completely
[20]
by fibrous tissue over time . In later studies utilizing more porous and less-constrictive stents, the space
between vein grafts and external stents was observed to become organized into a neoadventitia containing
[22]
macrophages, giant cells, and new microvessel growth . Within this neoadventitia, it was theorized that
accumulated macrophages were responsible for enhancing microvessel formation by releasing pro-
angiogenic cytokines, which would consequently reduce graft wall hypoxia to create a favorable chemotactic
gradient encouraging the migration of SMCs outwards and away from the intima. Indeed, while PDGF and
PCNA expression are decreased or absent from the media of stented vein grafts, high densities of PCNA-
positive nuclei and detectible PDGF have been observed in the neoadventitia, indicating ongoing
perivascular cell proliferation . Likewise, in vein grafts fitted with constrictive supports, it is possible that
[19]
the tighter-fitting sheaths disrupted neoadventitial microvascularity, explaining why they produced
paradoxical increases in intimal thickness. The dynamic interplay between stent materials, dimensions, and
neoadventitial formation highlights the intricate nature of vein graft remodeling, and has served to inform
modern-day strategies to prevent vein graft failure.

MODERN ADVANCEMENTS IN VEIN GRAFT FAILURE
The contemporary landscape of vein graft failure prevention has been marked by significant advancements
in the understanding of its pathology, which have in turn informed the development and optimization of
novel treatment strategies. In particular, the integration of computational modeling and molecular gene
expression profiles in vein grafts has yielded new insights into the complex interaction between
hemodynamic perturbations and cellular signaling. Concurrently, advancements in biomaterials
engineering and fabrication techniques have also produced novel external support compositions with
tunable biodegradability profiles, some of which are now being applied in ongoing human trials.

Computational modeling of vein graft adaptation
In modern studies of vein graft failure, computation fluid dynamics (CFD) has emerged as a valuable
method for studying the complex flow environments of saphenous veins in coronary surgery. Whereas
historical studies of vein graft flow have relied on simplified assumptions and idealized vessel geometries,
CFD models are able to incorporate patient-specific anatomy to investigate differential and oscillating
distributions of hemodynamic stresses within CABG conduits. Various hemodynamic parameters have
been developed to characterize the diverse flow environments between stented and unstented vein grafts,
including time-averaged wall shear stress (TAWSS) reflecting the frictional force of blood flow on the
endothelium, oscillatory shear index (OSI) representing the magnitude and direction oscillation of wall
shear stress , and relative residence time (RRT) indicating relative time duration that blood elements
[24]