Development and characterization of an ex vivo arterial long-term proliferation model for restenosis research.

Daniela Haase

doi:10.14573/altex.1503051

Abstract

One of the main limitations of percutaneous coronary interventions is the restenosis, occurring in small-diameter arteries, and efforts are high to find improved intracoronary devices to prevent in-stent-restenosis. Aim of this study was to produce a new in vitro test platform for restenosis research, suitable for long-term cell proliferation and migration studies in stented vessels. Fresh segments of porcine coronary arteries were obtained for decellularization and were then reseeded with human coronary artery endothelial (HCAEC) and human coronary artery smooth muscle cells (HCASMC). Subsequently, bare metal stents (BMS) and drug eluting stents (DES), respectively, were implanted and the segments were reseeded with HCAEC and HCASMC for up to three months. The stented segments were examined at time zero and after 2, 4, 6, 8 and 12 weeks by histochemical and immunohistochemical characterization and the reseeded areas before and after stent implantation were measured. We have found that cells formed multiple layers after three months, and the detection with both CD31 and a-smooth muscle actin specific antibodies showed that HCAEC and HCASMC are adherent and growing in several layers. Furthermore, we could show a significantly smaller proliferation area in DES (70% ± 3.5%), compared to BMS (17% ± 2.3%). These data are similar to animal and human studies. Therefore, this vessel model might appear as an initial benchmark for testing new anti-proliferative endovascular therapies and consequently helps to reduce animal experiments in this research area.

Highlights

Cardiovascular disease is the leading cause of mortality in Europe and the United States (Lloyd-Jones et al, 2009)
Despite a reduction of the restenosis rate in drug eluting stents (DES) compared with bare metal stents (BMS), late in-stent restenosis (ISR) has not been abolished (Stefanini and Holmes, 2013; Stettler et al, 2007; Akin et al, 2011)
The anti-proliferative effects are obtained at the cost of a significantly prolonged period of endothelialization of the stent struts and a dual anti platelet therapy (DAPT) of at least 6 months is indicated for DES

Summary

Introduction

Cardiovascular disease is the leading cause of mortality in Europe and the United States (Lloyd-Jones et al, 2009). Endovascular stents have lowered acute complication rates and improved long-term follow-up of coronary interventions, which are mainly limited by the occurrence of restenosis (Gruberg et al, 2000). Drug eluting stents (DES) have been developed, which slowly release anti-proliferative substances to the surrounding tissue (Katz et al, 2015). The mechanisms leading to DES restenosis are the development of neoatherosclerosis and local inflammatory processes triggered by the anti-proliferative substance, the polymer, or the stent struts themselves (Byrne et al, 2009; Pfisterer et al, 2006). The anti-proliferative effects are obtained at the cost of a significantly prolonged period of endothelialization of the stent struts and a dual anti platelet therapy (DAPT) of at least 6 months is indicated for DES

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