implantation-human-sized-coronary-stents-into-rat-abdominal-aorta

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of ...

University Hospital RWTH Aachen

Proliferation, migration and invasion of smooth muscle cells (SMCs) are essential pathogenic processes in the development of a broad spectrum of cardiovascular disorders, like arteriosclerosis, restenosis after percutaneous transluminal angioplasty and stent implantation as well as transplant vessel disease. As an in vitro model mimicking these processes, the Boyden chamber was employed to characterize the diverging migratory and invasive potentials of proliferating and nonproliferating human arterial SMCs (haSMCs). Using this model, differential gene expression of both phenotypes was analyzed by a cDNA array system (Clontech human cardiovascular array). With these arrays, 558 cardiovascular-associated genes could be compared. Further, gene expression was exactly quantified by real-time RT-PCR. Protein expression was analyzed by ELISA and Western blotting. In total, 47 genes were differentially expressed more than 1.5 times. Most of the differentially regulated genes in this study were associated with the extracellular matrix (ECM) and cell motility. In detail, the respective groups were matrix-organizing proteins, ECM proteins, cell adhesion proteins, extracellular communication and cytoskeleton motility proteins. Genes known to be differentially regulated during haSMC migration and invasion, like TIMP 2, TIMP 3, and MMP 3, were confirmed by the array data. Reduced expression of several cytoskeletal proteins, like vimentin, fibronectin, cytokeratins and beta1 integrin, was shown in the invasive phenotype. Further, angio-associated protein, alpha E-catenin and atrial brain natriuretic peptide receptor were downregulated whereas TFPI 2 was strongly upregulated in invasive haSMCs. In conclusion, several relevant potential candidate genes for the quiescent and the invasive SMC phenotype were identified and genes already known to be differentially regulated by previous analysis were confirmed.

Characterization of differential gene expression in quiescent and invasive human arterial smooth muscle cells.

Cardiovascular disease is the leading cause of death in the western and developing countries. Percutaneous transluminal coronary interventions have become the most prevalent treatment option for coronary artery disease; however, due to serious complications, such as stent thrombosis and in-stent restenosis (ISR), the efficacy and safety of the procedure remain important issues to address. Strategies to overcome these aspects are under extensive investigation. In this review, we summarise relevant milestones during the time to overcome these limitations of coronary stents, such as the development of polymer-free drug-eluting stents (DES) to avoid pro-inflammatory response due to the polymer coating or the developement of stents with cell-directing drugs to, simultaneously, improve re-endothelialisation and inhibit ISR amongst other techniques most recently developed, which have not fully entered the clinical stage. Also the novel concept of fully biodegradable DES featured by the lack of a permanent foreign body promises to be a beneficial and applicable tool to restore a natural vessel with maintained vasomotion and to enable optional subsequent surgical revascularisation.

Progress in interventional cardiology: challenges for the future.

Treatment of in-stent restenosis (ISR) is still a clinical challenge in interventional cardiology. Paclitaxel-coated balloons (PCBs) are an attractive therapeutic option for ISR. There are several different types of PCBs available for percutaneous coronary intervention, but to date, comparative data between different types of PCBs for the treatment of ISR are scarce.

Long-term clinical outcomes after treatment of stent restenosis with two drug-coated balloons.

The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR). In spite of a broad variety of animal models available, an ideal high-throughput model of ISR has been lacking. Apolipoprotein E (apoE) deficient rats enable the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. Whereas apoE deficient rats have been proposed as animal model of atherosclerosis, to date it is unknown whether they also develop pronounced ISR. We sought to assess ISR after abdominal aorta stent implantation in apoE deficient rats. A total of 42 rats (16 wildtype, 13 homozygous apoE and 13 heterozygous apoE rats) underwent abdominal aorta stent implantation. After 28 days blood samples were analyzed to characterize lipid profiles. ISR was assessed by histomorphometric means. Homozygous apoE rats exhibited significantly higher total cholesterol and low-density cholesterol levels than wildtype apoE and heterozygous apoE rats. ISR was significantly pronounced in homozygous apoE rats as compared to wildtype apoE (p = <0.0001) and heterozygous apoE rats (p = 0.0102) on western diet. Abdominal aorta stenting of apoE rats is a reliable model to investigate ISR after stent implantation and thus can be used for the evaluation of novel stent concepts. Apolipoprotein E (apoE) deficient rats have been proposed as animal model of atherosclerosis. We investigated the development of restenosis 28 days after stent implantation into the abdominal aorta of wildtype apoE, homozygous apoE and heterozygous apoE rats, respectively. Homozygous apoE rats exhibited significantly higher LDL and significantly lower HDL cholesterol levels compared to wildtype apoE and heterozygous apoE rats. Restenosis after stent implantation was significantly pronounced in western-diet-fed homozygous apoE rats, accompanied by a significantly increased neointimal thickness. Thus, apoE knockout rats exhibit elevated restenosis and might provide a novel tool for testing of innovative stent concepts.

Apolipoprotein E deficient rats generated via zinc-finger nucleases exhibit pronounced in-stent restenosis.

In patients with cardiovascular events, such as myocardial infarction or aortic dissection without known risk factors for cardiovascular disease, neoplastic disease should be considered as a differential diagnosis. In this report, we present a case of a 51-year old man with previously undiagnosed non-small lung cancer leading to fatal cardiovascular complications due to hemovascular spread, diagnosed post-mortem. This case illustrates the value of autopsy in unexpected deaths.

An unusual case of aortic metastasis from lung cancer.

We propose in vitro endothelialization of drug-eluting stents (DES) to overcome late stent thrombosis by directly introducing late-outgrowth human endothelial progenitor cells (EPCs) at the target site utilizing abluminal DES. Isolated EPCs were confirmed as late-outgrowth EPCs by flow cytometric analysis. Abluminally paclitaxel-loaded stents were seeded with different cell concentrations and durations to determine optimal seeding conditions, in both uncrimped and crimped configurations. The seeding yield was determined by evaluating the percent coverage of the stent struts' area. The EPC-seeded DES were exposed to arterial shear stress to evaluate the effect of high shear stress on EPCs. To investigate how much paclitaxel elutes during the seeding procedure, a pharmacokinetic analysis was performed. Finally, to validate the proof of concept, EPC-seeded DES were placed on a fibrin matrix with and without smooth muscle cells (SMCs) and cultured for 3 days under perfusion. The seeding procedure resulted in 47% and 26% coverage of the stent surface in uncrimped and crimped conditions, respectively. After the optimal seeding, almost 99% of drug was still available. When EPC-seeded DES were placed on a fibrin matrix and cultured for 3 days, the EPCs confluently covered the stent surface and spread to the surrounding fibrin gel. When EPC-seeded DES were placed on SMC-containing fibrin layers, cells in contact with the struts died. EPCs can be successfully seeded onto DES without losing drug-eluting capability, and EPCs exhibit sufficient proliferative ability. EPC-seeded DES may combine early re-endothelialization ability with the antirestenotic effectiveness of DES.

Article	Year
Characterization of differential gene expression in quiescent and invasive human arterial smooth muscle cells. Journal of vascular research\| PubMed ID: 12187124	2002
Progress in interventional cardiology: challenges for the future. Thrombosis and haemostasis\| PubMed ID: 25608683	2015
Long-term clinical outcomes after treatment of stent restenosis with two drug-coated balloons. Coronary artery disease\| PubMed ID: 30273183	2018
Apolipoprotein E deficient rats generated via zinc-finger nucleases exhibit pronounced in-stent restenosis. Scientific reports\| PubMed ID: 31796798	2019
An unusual case of aortic metastasis from lung cancer. Discoveries (Craiova, Romania)\| PubMed ID: 32309623	2020
Development of in vitro endothelialized drug-eluting stent using human peripheral blood-derived endothelial progenitor cells. Journal of tissue engineering and regenerative medicine\| PubMed ID: 32668066	2020

Felix Vogt

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