Risk Factors and Possible Mechanisms of Saphenous Vein Graft Failure After Coronary Artery Bypass Surgery

Risk Factors and Possible Mechanisms of Saphenous Vein Graft Failure After Coronary Artery Bypass Surgery

Coronary heart disease (CHD) is a complex metabolic syndrome characterized by atherosclerotic lesions in one or more coronary arteries. It is a leading cause of morbidity and mortality worldwide. Coronary artery bypass grafting (CABG) is the gold standard for invasive treatment of severe CHD, particularly in cases of triple-vessel disease and left main disease. The saphenous vein (SV) is commonly used in CABG due to its sufficient length and ease of harvesting. However, saphenous vein graft (SVG) failure remains a significant issue, with approximately 20% of SVGs failing within the first year after surgery and a 10-year patency rate of only 60%.

The failure of vein grafts is influenced by multiple risk factors, including endothelial cell (EC) dysfunction, instantaneous shear stress changes, the structural characteristics of SVs, and surgical techniques. ECs form a thin layer of specialized epithelial cells located between the blood and the blood vessel wall. Under normal conditions, ECs act as a barrier, maintaining vascular homeostasis by synthesizing and releasing various mediators. These mediators include vasodilators such as nitric oxide (NO) and prostacyclin, vasoconstrictors like angiotensin-converting enzyme and endothelin, growth factors such as insulin-like growth factor and transforming growth factor, antithrombotic factors like thrombomodulin and heparin, and procoagulant factors such as von Willebrand factor (vWF) and thromboxane A2 (TXA2). Additionally, ECs release inflammatory mediators like interleukin (IL)-1, IL-6, and IL-8, which play roles in inflammatory responses. When ECs are damaged, a complex network of adhesion, chemotaxis, and inflammatory responses is triggered, affecting vascular smooth muscle cells (VSMCs), platelets, and peripheral leukocytes through autocrine, paracrine, and endocrine mechanisms.

Harvesting SVs results in ischemia-reperfusion injury, which can cause ultrastructural changes in ECs. Studies using transmission electron microscopy have shown that ECs in canine veins exhibit changes after just 30 minutes of ischemia. Longer ischemic times are associated with more severe EC damage. EC dysfunction leads to decreased activity of endothelial NO synthase and a reduction in NO production. This dysregulation of NO balance impairs vasodilation, increases reactive oxygen species (ROS) production, and promotes the proliferation and migration of VSMCs. The Rho/Rho-kinase pathway negatively regulates endothelial NO synthase and is involved in intimal hyperplasia. Long-term oral Rho-kinase inhibition has been shown to suppress VSMC proliferation and intimal thickening in vein grafts in rabbit models, suggesting a potential treatment for vein graft failure.

Instantaneous shear stress changes are another significant risk factor for SVG failure. Under normal conditions, the wall shear stress of SVs ranges from 1 to 6 dyn/cm², with a hydrostatic pressure of 5 to 10 mmHg. After implantation, SVs experience much higher wall shear stress (10–70 dyn/cm²) and hydrostatic pressure (120/80 mmHg). The endothelium is highly sensitive to these hemodynamic changes, and the immediate increase in shear stress and pressure can cause EC damage and exfoliation, further compromising the vascular endothelial barrier.

The structural differences between SVs and arteries also contribute to SVG failure. SVs have a narrower medial layer composed primarily of collagen, fenestrated elastic laminae, less elastin, and fewer VSMCs compared to arteries. Ephrin B2 and ephrin B4 are key factors in arteries and veins, respectively. Studies have shown that EphB4 expression decreases during SVG adaptation in humans and adult rats. Reduction in EphB4 expression in ECs in a mouse vein graft model leads to diminished proliferation and migration of ECs and VSMCs, indicating that the loss of EphB4 plays a role in vein graft adaptation. Stimulating EphB4 function may be a potential strategy for inhibiting venous neointimal hyperplasia in human clinical trials.

Vascular endothelial growth factors (VEGFs) are a subfamily of growth factors involved in vasculogenesis and angiogenesis. VEGF-A plays a critical role in downregulating EphB4 expression in adult venous ECs without inducing ephrin B2 expression. These changes in ECs in vitro mimic the changes observed during vein graft adaptation to the arterial environment in vivo. However, the role of VEGFs in grafted veins is complex. In the early post-implantation period, VEGF may act as a beneficial repair factor for EC damage. In the long term, increased VEGF expression may contribute to VSMC proliferation and neointimal formation. The mechanism of VEGF action in vein grafts requires further investigation.

Surgical techniques also play a crucial role in SVG failure. The “no-touch” technique of SV harvesting has been shown to improve both short-term and long-term patency of SVGs. Perivascular adipose tissue releases cytokines, adipokines, and inflammatory factors through autocrine and/or paracrine pathways, regulating vascular tone, VSMC proliferation and migration, atherosclerosis, and restenosis. The “no-touch” technique preserves perivascular adipose tissue, providing a protective medium for SVs and maintaining EC integrity and function. Studies comparing “off-pump” and “on-pump” CABG have shown that graft patency after one year is significantly lower in “off-pump” CABG. Additionally, endoscopic vein harvesting is associated with lower SVG patency after one year compared to open-vein harvesting.

Vein graft failure is the result of a complex pathophysiological process involving thrombosis, intimal hyperplasia, atherosclerosis, and inflammation. Thrombosis is the primary cause of early SVG failure, typically occurring within the first month after CABG. After SVG, intimal damage leads to EC denudation, exposing the subendothelial extracellular matrix to flowing blood. Platelets are activated by subendothelial extracellular matrix proteins, including laminin, fibronectin, vitronectin, and collagen. Activated platelets release vasoactive substances such as growth factors, chemotactic factors, IL-1β, and thrombin, further stimulating thrombosis. This process is closely related to EC dysfunction and instantaneous shear stress changes in SVs.

Intimal hyperplasia is the main cause of delayed SVG failure, occurring between one and twelve months after CABG. Abnormal proliferation and migration of VSMCs play a critical role in intimal hyperplasia. After EC injury, various cell types, including ECs, platelets, and inflammatory cells, release mediators that promote VSMC proliferation and migration. EC damage and dysfunction also lead to extracellular matrix protein deposition, further inducing VSMC migration and proliferation.

Atherosclerosis is the leading cause of late SVG failure, occurring one year or more after CABG. Foam cells and intimal thickening appear one year after SVG, with necrotic cores developing between two and five years. More than five years after SVG, necrotic cores, intra-plaque hemorrhage, and fibrous plaque rupture are observed in the lumen. The pathogenesis of atherosclerosis involves foam cell accumulation, cellular proliferation, inflammatory cell infiltration, fibrous plaque formation, intra-plaque hemorrhage, and plaque rupture. Grafted SVs are more prone to developing atherosclerosis, with more rapidly progressing pathological changes compared to coronary arteries.

Inflammation plays a significant role in the pathological process of vein graft failure. SV distention pressure is correlated with inflammatory markers such as toll-like receptors 2 and 4, platelet endothelial cell adhesion molecule (PECAM), vascular cell adhesion molecule, and intercellular cell adhesion molecule. Toll-like receptors activate monocyte chemoattractant protein-1 (MCP-1), inducing cytokine release through the myeloid differentiation primary response protein 88 – nuclear factor-kB pathway. Inhibition of nuclear factor-kB can suppress inflammatory responses and VSMC accumulation in neointimal hyperplasia in rabbit models. Arterialization of vein grafts activates p38 mitogen-activated protein kinases (MAPKs) in canine models, and p38 MAPK inhibitors significantly reduce intimal, medial, and adventitial thickening in rat models. Anti-inflammatory treatments, such as local blockade of the MCP-1/CCR-2 signaling pathway, have been shown to attenuate inflammation, proliferation, and neointimal formation in dogs with vein grafts. Low levels of anti-phosphorylcholine immunoglobulin M, an anti-inflammatory mediator, are associated with vein bypass graft failure in patients with chronic peripheral arterial disease.

In conclusion, SVG failure is a multifactorial problem involving thrombosis, intimal hyperplasia, atherosclerosis, and inflammation. While the mechanisms of inflammation in vein graft failure are not fully understood, recent studies suggest potential anti-inflammatory therapies that could improve SVG patency. Further research is needed to fully elucidate these mechanisms and develop effective treatments for vein graft failure.

doi.org/10.1097/CM9.0000000000000872

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