The Mechanisms of Restenosis and Relevance to Next Generation Stent Design

Abstract

Stents are lifesaving mechanical devices that re-establish essential blood flow to the coronary circulation after significant vessel occlusion due to coronary vessel disease or thrombolytic blockade. Improvements in stent surface engineering over the last 20 years have seen significant reductions in complications arising due to restenosis and thrombosis. However, under certain conditions such as diabetes mellitus (DM), the incidence of stent-mediated complications remains 2-4-fold higher than seen in non-diabetic patients. The stents with the largest market share are designed to target the mechanisms behind neointimal hyperplasia (NIH) through anti-proliferative drugs that prevent the formation of a neointima by halting the cell cycle of vascular smooth muscle cells (VSMCs). Thrombosis is treated through dual anti-platelet therapy (DAPT), which is the continual use of aspirin and a P2Y₁₂ inhibitor for 6-12 months. While the most common stents currently in use are reasonably effective at treating these complications, there is still significant room for improvement. Recently, inflammation and redox stress have been identified as major contributing factors that increase the risk of stent-related complications following percutaneous coronary intervention (PCI). The aim of this review is to examine the mechanisms behind inflammation and redox stress through the lens of PCI and its complications and to establish whether tailored targeting of these key mechanistic pathways offers improved outcomes for patients, particularly those where stent placement remains vulnerable to complications. In summary, our review highlights the most recent and promising research being undertaken in understanding the mechanisms of redox biology and inflammation in the context of stent design. We emphasize the benefits of a targeted mechanistic approach to decrease all-cause mortality, even in patients with diabetes.

Keywords: drug-eluting stents; inflammation; neointimal hyperplasia; redox; restenosis.

Figure 2

Redox processes in endothelial cells (ECs). Under physiological conditions, coupled eNOS synthesises nitric oxide (NO) and l-citrulline from l-arginine, with NO secretion and interaction with VSMCs. Nox1 is the predominant isoform of the Nox enzymes responsible for superoxide (O⁻) production, required for physiological processes. Superoxide levels are controlled by the superoxide dismutases (SOD) that convert superoxide to hydrogen peroxide (H₂O₂), which is then neutralised to water by glutathione peroxidase (GPx) enzymes. GPx1 is the most abundant cytosolic isoform shown to play an important role in ECs [62]. Under pathological conditions, uncoupled eNOS no longer produces NO and instead synthesises superoxide. Superoxide then interacts with NO to form peroxynitrite (ONOO⁻), thus reducing the bioavailability of NO. Apart from hydrogen peroxide neutralisation, GPx1 can also convert peroxynitrite to nitrite (NO₂⁻). Under pathological conditions, such as in the setting of diabetes, the activity of GPx1 declines. This, in turn, leads to an increase in reactive oxygen species (ROS) such as H₂O₂, ONOO⁻ and lipid peroxides which promote endothelial dysfunction.

Figure 1

Inflammatory processes in the vasculature after stenting. Healthy endothelial cells (ECs) secrete nitric oxide (NO), which then interacts with vascular smooth muscle cells (VSMCs) to modulate vasoconstriction. After stenting, ECs are denuded from the vessel wall, and pro-inflammatory cytokines such as IL-6, TNFα and IL-1β are secreted by circulating monocytes and activate remaining ECs. More monocytes are then recruited to the site of injury by these cytokines and, through the interaction of Mac-1/LFA-1 with ICAM-1, begin firm rolling and attachment to the endothelium before transmigration into the subintimal space. When activated, ECs attract platelets to the stented region, where they begin to form a thrombus (clot) with fibrin molecules. Activated ECs also begin expressing NF-κB. This, in turn, downregulates NO production, and in combination with other factors, activates VSMCs, which begin to shift to a highly proliferative and migratory phenotype, thereby contributing to neointimal hyperplasia and restenosis. A late process (around 1–2 years) is neoatherosclerosis, where macrophages take up oxidised-LDL (Ox-LDL) to form foam cells which contribute to the development of an atherosclerotic plaque (figure assets from Servier Medical Art—smart.servier.com).

Figure 3

Covered and uncovered stent struts. (A-1), strut coverage with 2 layers of vascular smooth muscle cells and a monolayer of endothelial cells. (B-1), uncovered strut with coverage of inflammatory cells. (A-2,B-2) higher-powered images highlighting strut coverage (Adapted from [184]).