Abstract
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.
Highlights
The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR)
In animals receiving western diet, body weight was higher than in animals on normal diet (503.21 ± 9.12 g vs. 549.28 ± 17.55 g; p = 0.0368). This was especially pronounced in heterozygous Apolipoprotein E (apoE)+/− rats (628.33 ± 32.91 g on western diet vs. 497.00 ± 19.04 g on normal diet; p = 0.0415, Fig. 2f)
We observed a generally lower ISR as compared to previous studies, we found homozygous apoE−/− rats to exhibit significantly more restenosis, a greater neointimal area and neointimal thickness as compared to wildtype apoE+/+ rats and heterozygous apoE+/− rats on western diet
Summary
The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR). Whereas apoE deficient rats have been proposed as animal model of atherosclerosis, to date it is unknown whether they 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. 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. Transgenic or knockout strains allow for the study of phenotypes of acquired or heritable metabolic disorders As both rats and mice do not spontaneously form hemodynamically significant stenoses, the apolipoprotein E deficient mouse model has been broadly used to study cardiovascular diseases[20,21,22]. Neointima was pronounced 28 days after stent deployment and consisted mainly of smooth muscle cells in a collagen and elastin rich matrix
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