Modelling the Effect of a Functional Endothelium on the Development of In-Stent Restenosis

Abstract

Treatment of stenosed coronary arteries by balloon angioplasty and stenting results in arterial injury including severe damage to the endothelium at the site of treatment and initiates a complex cascade of inflammatory processes that may lead to the development of in-stent restenosis (ISR). Many clinical and biological factors involved in the progression of restenotic lesions have been studied in detail over the past few years but the mystery behind the pathophysiological mechanisms of this disease is still unresolved. In the present work, the effects of re-endothelialization and nitric oxide release on neointimal growth are investigated in-silico using a two dimensional multi-scale model of ISR. The effect of stent deployment depths on the development of ISR is studied as a function of time after stenting. Two dimensional domains were prepared by deploying bare metal stent struts at three different deployment depths into the tissue. Shear stress distribution on endothelial cells, obtained by blood flow simulations, was translated into nitric oxide production that keeps the smooth muscle cells in quiescent state. The cellular growth trends were plotted as a function of time and the data indicate a positive correlation between the neointimal growths and strut deployment depths in the presence of a functional endothelium, in qualitative agreement with in-vivo data. Additionally, no ISR is observed if a functional endothelium appears much earlier.

Wall shear stress in the development of in-stent restenosis revisited. A critical review of clinical data on shear stress after intracoronary stent implantation

“…It is also crucial to comprehend that the newly regenerated endothelial layer is often dysfunctional [40]. This fact can play a key role in the restenotic process, when the uncontrolled neointimal formation is not stopped after the shear stress-induced "normal" re-endothelialization increased the flow velocity by decreasing the lumen diameter.…”

Noninvasive Molecular Ultrasound Monitoring of Vessel Healing After Intravascular Surgical Procedures in a Preclinical Setup

“…However, the patient's age, general immune state, comorbidities, such as diabetes mellitus, and the different size of the plaque and injured area can strongly influence the speed of regeneration and degree of inflammation. 16,17 Thus, there seems to be a clear need for a reliable diagnostic assessment of endothelial regeneration, as well as for the individualization of postinterventional anticoagulant and anti-inflammatory therapy.…”

Endothelial repair process and its relevance to longitudinal neointimal tissue patterns: comparing histology with in silico modelling

“…NO is produced by a functional endothelium in response to fluid shear stresses, higher concentrations of NO are assumed to arrest the cell cycle during the G1 phase and return the cell to a quiescent state. Further details related to the formulation of the cell cycle have been explained in our previous publication [12].…”

“…Therefore, we assume that any endothelium which is not yet mature/functional does not play a significant role. The generation of NO from shear stress has been estimated by extrapolating the data provided by Guo et al [30], these details are reported in our previous paper [12]. Nakazawa et al [31] observed the time course of endothelial regeneration in stented porcine coronary arteries and assessed its functionality by means of platelet endothelial cell adhesion molecule (PECAM-1).…”