The saphenous vein was the first bypass vessel used in coronary artery bypass grafting (CABG) and is still widely used in clinical practice. The patency rate at 1 year and 61% at 10 years after saphenous vein bypass has been reported in the literature, while the 10-year patency rate for the internal mammary artery is 85%. Acute bypass vessel failure is mainly influenced by technique and thrombosis, whereas late failure (more than 1 month after CABG) is the result of intimal hyperplasia and the consequent accelerated development of atherosclerosis. A review of the pathogenesis and treatment of intimal hyperplasia in venous grafts is presented to provide clinical assistance.
Intimal hyperplasia and vein graft restenosis
Endothelial hyperplasia occurs during the closure of the arterial duct in normal physiological processes and in different diseases in pathological processes. At the cellular level, endothelial hyperplasia includes the continuous proliferation and migration of smooth muscle cells (VSMC) with deposition of extracellular matrix, which can lead to significant endothelial by-pass lesions and ultimately to luminal stenosis and thrombosis. Endothelial hyperplasia occurring after CABG, angioplasty, arteriovenous fistula formation, and grafting is known as accelerated endothelial hyperplasia (AIH).
Risk factors for AIH include trauma, hemodynamic changes, vasospasm, and ischemia, which are also the underlying causes of vein graft restenosis. In contrast, most occlusions of late venous bypass vessels (more than 5 years after graft surgery) are associated with atherosclerosis.
Pathogenesis of endothelial hyperplasia
The endothelium is the main regulator of the dynamic homeostasis of the vessel wall, controlling vascular tone, blood coagulation, leukocyte aggregation and angiogenesis. Although how resting intact endothelium inhibits AIH has not been fully elucidated, experiments have demonstrated that endothelial damage with or without mid-layer injury is associated with the development of AIH. Mechanical and physical trauma leads to endothelial denudation and is an important stimulus for endothelial activation after CABG, and the level of AIH is directly related to endothelial denudation. In CABG, physical trauma is mainly attributed to intraoperative dilation of the lumen, trauma to the surgical anastomosis, and altered hemodynamics. These traumas are closely related to inflammation, VSMC proliferation and migration, and extracellular matrix deposition, in addition to thrombosis. Based on these factors, regeneration of the endothelium becomes important.
Shear forces acting parallel to the vessel wall are also associated with endothelial proliferation. High shear gradients affect the structure and function of the venous bypass endothelium. The correlation between low shear force and AIH has also been reported in detail. Therefore, the vasculature needs the right shear force and slope, otherwise both will develop AIH.
Endothelial cells are mainly affected by shear, whereas VSMC are mainly affected by blood pressure. there are various receptors on the VSMC cell membrane that can sense changes in external mechanical stress, such as adhesion patches, integrins, and cell junctions that can redirect mechanical signals from extracellular to intracellular and initiate complex signal transduction cascade reactions that lead to certain functional changes within the cell. The occurrence of venous bypass restenosis is closely related to mechanical stress.
It is now well established that vasoactive products are influenced by blood flow morphology and their expression is elevated when endothelial cells are exposed to shear forces. The mechanism of hemodynamic influence on AIH has also been reported.
Treatment of endothelial hyperplasia
1. Thrombosis and coagulation
Platelet activation occurs rapidly after venous grafting, and the degree of activation correlates with the degree of vascular damage, which can lead directly to thrombosis and early bypass vessel occlusion. Aspirin is the longest used and most classic antiplatelet drug, which can improve the patency rate 1 year after CABG, but many patients clinically develop early bypass vessel occlusion even with the “proper” dose of aspirin, called “aspirin resistance”. “The mechanism of this phenomenon is still unclear. It has been shown that aspirin does not inhibit endothelial proliferation.
Clopidogrel, a member of the thienopyridine family, is widely used in clinical practice and can inhibit platelet adhesion and mitogenic signaling pathways. However, it has also been demonstrated that the combination of clopidogrel and aspirin after CABG did not significantly reduce endothelial hyperplasia compared with aspirin alone. Because the observation period is only 1 year, the trial results are still somewhat controversial.
2. VSMC proliferation and migration
VSMC is the main component of neoplastic endothelium, and its proliferation and phenotypic switch between contractile and secretory phenotypes are caused by the stimulation of many growth factors, including basic fibroblast growth factor (bFCF), platelet-derived factor (PDGF), epithelial growth factor (EGF), and transforming growth factor-β (TGF-β). The receptors for the first 3 of these have tyrosine kinase activity. In animal models, topical administration of tyrosine phosphorylation inhibitors (specifically targeting PDGF) resulted in a significant reduction in endothelial hyperplasia.
More recent studies have focused on signaling pathways, i.e., pathways linking external mitogenic stimuli to pathological alterations in VSMC cell cycle in venous bypass vessels. Thus, the increased level of therapeutic inhibition of AIH requires a deeper understanding of its interactions in the regulation of VSMC proliferation and migration.
Phosphatase-tensin analogs (PTEN) play an important role in cell cycle regulation, and it has been reported that regulation of the PI3K-AKT/PKB signaling pathway by PTFN can treat venous bypass failure after CABG.
Intact extracellular matrix can act as a physical barrier and signaling pathway inhibitor to prevent VSMC migration from occurring. The signaling molecules associated with VSMC migration have been most extensively studied with matrix metalloproteinases (MMPs), whose production is stimulated by both growth factors and inflammatory cytokines and which are closely associated with cell proliferation. Recently, it has been reported that transfection of MMP3 gene with adenoviral vector can effectively inhibit VSMC migration and endothelial proliferation in rabbit venous grafts, which is expected to be applied in clinical practice. In addition, calcium-dependent adhesion protein (CDH11) expression is increased in venous bypass SMCs, and its expression can be inhibited using anti-CDH11 antibody or siRNA interference techniques, and the proliferation and migration of SMCs can be suppressed.
The important role of VSMC proliferation and migration in altered vascular pathology makes it a therapeutic target. Studies have included many compounds including MAPK inhibitors20 that can specifically act on intracellular and intercellular signaling pathways associated with VSMC proliferation and migration, but are still in the early stages of research.
Rapamycin is a macrolide immunosuppressant that inhibits VSMC proliferation and migration induced by mechanical injury or immune response, myocardial hypertrophy due to angiotensin II, and ICAM-1 expression due to tumor necrosis factor (TNF)-α. The application of this drug stent in intimal hyperplasia of venous bypass is mainly focused on the application of this drug stent after bypass vessel occlusion. To reduce the side effects of systemic administration of rapamycin, topical administration has been attempted. While other anti-proliferative drugs such as paclitaxel, 5-fluorouracil (5-FU), and FK778 have been reported to inhibit endothelial hyperplasia.
3.Inflammation
The subendothelial inflammatory response is central to the pathogenesis of atherosclerosis and has been described as a hallmark of the restenosis process. The early stage of the inflammatory response is leukocyte aggregation. More specifically, there is a strong link between the subendothelial inflammatory response and VSMC function, which is capable of synthesizing many types of bioactive regulators that regulate vasoconstriction and diastole as well as proliferation, apoptosis and inflammation.
The concept of anti-inflammatory drugs for AIH is relatively new. It was demonstrated that short-term use of dexamethasone (7 days postoperatively) can effectively inhibit endothelial proliferation by reducing inflammatory cytokines without complications such as poor wound healing. In rat experiments, viral transfection of the TGF-β antisense gene reduced the thickness of endothelial proliferation and attenuated the expression of MCP-1. Complement is an important component of the immune system and is involved in the inflammatory response. Intervention of C3 activity by antibodies against complement receptor-related genes can reduce the thickness of endothelial hyperplasia and reduce the inflammatory response.
4.Extravascular stent
The effect of extravascular stents on venous bypass was first reported by Parsonnet in 1963. Since then, a large number of studies have shown that placement of extravascular stents around bypass vessels can reduce vascular neointimal hyperplasia, prevent the occurrence of venous bypass atherosclerosis and improve the long-term patency of venous bypass, and great progress has been made in terms of its materials, mechanism of action and clinical application. In recent years, the effects of drug-based extravascular stents on endothelial hyperplasia have also been reported in the literature. The materials of extravascular scaffolds include biodegradable organisms (e.g., biogel, chitosan), polymer composites, and radiolucent alloys; their mechanisms of action include promotion of endothelial vascular proliferation, reduction of cytokine and growth factor release, promotion of VSMC migration to the endothelium, and inhibition of neural reorganization. In addition, it has also been demonstrated that extravascular stents, whether 4mm, 6mm or 8mm in diameter, produce approximately the same effect on the inhibition of endothelial proliferation.
5.Other treatments
Nitric oxide (NO) has anti-thrombotic, vasodilatory and anti-proliferative properties; eNOS is a biochemical enzyme that promotes NO synthesis. Early in transplantation, NO expression in venous bypass decreases, leading to endothelial hyperplasia, and the Rho/Rho-kinase signaling pathway can negatively regulate eNOS, thus interfering with endothelial hyperplasia. Animal experiments have shown that eNOS gene transfection, Rho-kinase inhibitors, L-arginine, and statins can effectively inhibit endothelial hyperplasia. A recent rat vein graft experiment showed that in vitro immersion of venous bypass vessels in CO-containing lactate prior to grafting also inhibited endothelial proliferation, probably by activating hypoxia-inducible factor-1 and thereby increasing vascular endothelial growth factor expression.
Conclusion
Currently, restenosis of venous grafts remains a major challenge in coronary surgery. Although great progress has been made in reducing graft failure through the application of new technologies such as the genetic ding process for natural bypass vessels, this problem is still not fully resolved. We must continue to search for a more effective treatment to reduce or prevent neoplastic endothelium formation. It is believed that through an in-depth understanding of the complex cellular-molecular mechanisms involved in restenosis and the continuous search for a suitable route of administration, this challenge will definitely be solved and the prospects are worth looking forward to.