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.

Human Adipose-Derived Mesenchymal Stem Cell-Secreted Extracellular Matrix Coating on a Woven Nanotextile Vascular Patch for Improved Endothelial Cell Response

“…In this study, the ECM deposited onto the patches can provide all the necessary structural and functional cues that would facilitate ECs to attach and proliferate, forming an EC monolayer relatively faster compared to the bare patches. This in turn can prevent smooth muscle cell adhesion onto the vascular biomaterial surface …”

Restenosis after Coronary Stent Implantation: Cellular Mechanisms and Potential of Endothelial Progenitor Cells (A Short Guide for the Interventional Cardiologist)

“…Histamine released from platelets and mast cells may also cause intimal hyperplasia, as the levels of this mediator were shown to increase by 20 to 90 times in a porcine model of endothelial injury, while in vitro histamine potentiated the PDGF-stimulated proliferation of cultured SMCs [21]. Platelet-derived interleukin-1 increases production of proinflammatory interleukin-6 and interleukin-8, respectively, stimulating SMC migration by actin polymerization and tyrosine phosphorylation of focal adhesion-associated cytoskeletal protein and the proliferation of SMCs [22]. In this context, thrombin also has potent mitogen effects, and the immunosuppressive effect of the drug eluted might slow tissue repair reaction and fibrin removal.…”

“…In the vessel wall, inflammatory responses to the foreign body and the antiproliferative effect of the drug eluted by the stent lead to delayed reendothelialization. Exposure of adhesion molecules (P-selectin, intercellular adhesion molecule-1) stimulates the recruitment of monocytes and the subsequent secretion of inflammatory cytokines (interleukins 6 and 8), resulting in the influx of neutrophils, monocytes and macrophages into the subendothelial space [22]. In line with this, elevated levels of monocytes (odds ratio 1.44, 95% CI: 1.23-1.68, p < 0.001) and eosinophils (odds ratio: 1.22, 95% CI: 1.09-1.36, p = 0.001) at three months after PCI are predictors of late in-stent restenosis after drug-eluting stent implantation [28].…”

Validation of an ex vivo Flow Model Including Magnetic Resonance Imaging to Study the Effects of Endovascular Treatments on the Arterial Wall

“…Moreover, there is compelling evidence that acute endothelial damage caused by revascularization is related to the late-onset occurrence of restenosis [6, 7]. Hence, strategies for preventing endothelial damage can potentially improve patients’ outcomes.…”