Severity Of Intimal Hyperplasia Research Articles

CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen.

CXC motif chemokine receptor 4 (CXCR4) blockade is pursued as an alternative to mesenchymal stem cell treatment in transplantation based on our previous report that burixafor, through CXCR4 antagonism, mobilizes immunomodulatory mesenchymal stem cells. Here, we explored the efficacy of combining mycophenolate mofetil (MMF)-based immunosuppressants with repetitive burixafor administration. Swine heterotopic cardiac allograft recipients received MMF and corticosteroids (control, n = 10) combined with burixafor as a 2-dose (burixafor2D, n = 7) or 2-dose plus booster injections (burixafor2D + B, n = 5) regimen. The efficacy endpoints were graft survival, freedom from first acute rejection, and the severity of intimal hyperplasia. Each specimen was sacrificed either at its first graft arrest or after 150 days. After 150 days, all specimens in the control group had died, but 28.5% of the burixafor2D group survived, and 60% of the burixafor2D + B group survived (P = 0.0088). Although the control group demonstrated acute rejection at a median of 33.5 days, the burixafor2D + B group survived without acute rejection for a median of 136 days (P = 0.0209). Burixafor administration significantly attenuated the incidence rate of acute rejection (P = 0.002) and the severity of intimal hyperplasia (P = 0.0097) at end point relative to the controls. These findings were associated with reduced cell infiltrates in the allografts, and modulation of C-reactive protein profiles in the circulation. The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans.

Healing of two microarterial anastomoses with diameter mismatch

BackgroundThe use of fascial perforating vessels as recipients for microvascular composite tissue autotransplants has led to vessel diameter discrepancy becoming an increasingly common finding. Little evidence, however, is available to direct the choice of anastomotic technique where a discrepancy exists. We have been studying two methods of anastomosing arteries where a small-to-large discrepancy exists—a 45° section of the smaller vessel, and invaginating the smaller vessel inside the larger. As part of this work, this study examines intimal hyperplasia and healing of the two methods. Materials and methodsA previously described paired Wistar rat femoral axis model was used. Anastomoses were performed, one on each side, and specimens were harvested in groups at 24 h, 1 wk, 6 wk, and 8 mo. Inflammation, necrosis, and fibrosis in each layer of the vessel wall and intimal hyperplasia were each scored by an assessor blinded to the group and anastomotic technique. ResultsSignificant differences in healing were found. The invagination technique induced less inflammation, and caused less endothelial and medial necrosis than the oblique cut end-to-end method. Intimal hyperplasia was most pronounced at 6 wk, but no evidence of a difference in the severity of intimal hyperplasia between the two methods was found. ConclusionsThe invaginating anastomosis causes less inflammation and less vessel wall necrosis than the oblique end-to-end method in this model. This finding, alongside results from previous work, suggests that this is the better method to deal with a small-to-large microarterial diameter discrepancy in the range 1:1.5 to 1:2.5.

Paeonia lactiflora Extract Attenuating Cerebral Ischemia and Arterial Intimal Hyperplasia Is Mediated by Paeoniflorin via Modulation of VSMC Migration and Ras/MEK/ERK Signaling Pathway.

Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which is used to treat smooth muscle spasms and pain and to protect the cardiovascular system. The objective of this study was to determine if Paeonia lactiflora would be protective in rodent models of cerebral ischemia and arterial intimal hyperplasia. Paeonia lactiflora extract (PLex) and paeoniflorin (PF) significantly attenuated cerebral infarction in ischemia/reperfusion injury rats and the severity of intimal hyperplasia in mice where the carotid artery was ligated. PLex and PF reduced PDGF-stimulated VSMC proliferation and migration in a dose-dependent manner by MTT, wound healing, and transwell assays. PF significantly reduced protein levels of Ras, MEK, p-MEK and p-ERK, but not MMP-2 and MMP-9. In summary, Paeonia lactiflora reduced cerebral ischemia and arterial intimal hyperplasia which were mainly made via the intermediary of PF. The protective effect of PF was related to the modulation of the Ras/MEK/ERK signaling pathway.

Urinary trypsin inhibitor reduced neointimal hyperplasia induced by systemic inflammation after balloon injury in rabbits

The aims of this study were to evaluate the effect of urinary trypsin inhibitor (UTI) on the regulation of inflammatory cytokines induced by lipopolysaccharide (LPS) and the reduction of neointimal formation in rabbits. Rabbits subjected to iliac artery balloon injury were randomly divided into three groups: control group (balloon injury), LPS group (LPS+balloon injury) and UTI group (UTI+LPS+balloon injury). Systemic markers of inflammation (serum IL-1β and TNF-α levels measured by ELISA) were increased after LPS administration. Arterial nuclear factor-κB (NF-κB/p65) at 28days after injury was 31.50±7.08% of total cells in controls and 73.50±6.90% in LPS group (P<0.05). Morphometric analysis of the injured arteries at 28days revealed significantly increased luminal stenosis (45.81±5.31 vs 27.93±2.85%, P<0.05) and neointima-to-media ratio (1.40±0.15 vs 0.68±0.12, P<0.05) in LPS-treated animals compared with controls. This effect was reduced by UTI administration. Serum IL-1β and TNF-α levels and NF-κB/p65 expression were significantly increased in correlation with the severity of intimal hyperplasia and inhibited by UTI. Systemic inflammatory response concurrently with arterial vascular injury facilitated neointimal formation. UTI reduced neointimal hyperplasia by regulating inflammatory response and could be considered as a potential anti-restenosis supplement.

Intimal Hyperplasia in Rats after Subcutaneous Injection of a Somatostatin Analog

The somatostatin analog octreotide was administered to male and female Sprague-Dawley rats by subcutaneous injection for thirteen weeks at 0 (saline control), 0 (placebo control [mannitol and lactic acid; pH 4.2]), 1.25 mg/kg/day and 2.5 mg/kg/day to explore its potential effect on cutaneous vascular morphology. The placebo caused an increase in the incidence of intimal hyperplasia compared to saline controls in female rats; octreotide increased the incidence and severity of intimal hyperplasia in males and females. Intimal hyperplasia consisted of increased numbers of cells located between the endothelial cell layer and the internal elastic lamina. Severity was based on the degree of compromise of the vascular lumen (regardless of vessel size and number), with severely affected vessels having no visible lumen. Intimal hyperplasia in rats treated with octreotide was considered to be an unexpected and adverse finding, given that this compound and other somatostatin analogs have been investigated as reducers of intimal proliferation or restenosis after angioplasty in humans and that no such lesion has been reported in the literature for this class of compound to date. The induction of intimal hyperplasia by the placebo is also a notable finding; this may be because of the low pH of the formulation.

Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits.

Emerging data indicate that the inflammatory response after mechanical arterial injury correlates with the severity of neointimal hyperplasia in animal models and postangioplasty restenosis in humans. The present study was designed to examine whether a nonspecific stimulation of the innate immune system, induced in close temporal proximity to the vascular injury, would modulate the results of the procedure. Methods and Results- Rabbits subjected to iliac artery balloon injury (balloon denudation with or without stent deployment) were injected twice with a bacterial lipopolysaccharide (LPS) (500 ng/rabbit) before and after surgery. The dose was chosen to be sufficient to induce systemic inflammation but not septic shock. A systemic marker of inflammation (serum interleukin-1beta levels measured by ELISA) and monocytic stimulation (CD14 levels on monocytes measured by flow cytometry) were increased after LPS administration. Arterial macrophage infiltration at 7 days after injury was 1.7+/-1.2% of total cells in controls and 4.2+/-1.8% in LPS-treated rabbits (n=4, P<0.05). Morphometric analysis of the injured arteries 4 weeks after injury revealed significantly increased luminal stenosis (38+/-4.2% versus 23+/-2.6, mean+/- SEM; n=8, P<0.05) and neointima-to-media ratio (1.26+/-0.21 versus 0.66+/- 0.09, P<0.05) in LPS-treated animals compared with controls. This effect was abolished by anti-CD14 Ab administration. Serum interleukin-1beta levels and monocyte CD14 expression were significantly increased in correlation with the severity of intimal hyperplasia. LPS treatment increased neointimal area after stenting from 0.57+/-0.07 to 0.77+/- 0.1 mm(2) and stenosis from 9+/-1% to 13+/-1.7% (n=5, P< 0.05). Nonspecific systemic stimulation of the innate immune system concurrently with arterial vascular injury facilitates neointimal formation, and conditions associated with increased inflammation may increase restenosis.

Stapled versus Hand-Sewn Vascular Anastomoses

Objective: Narrowing of vascular anastomoses is a frequently encountered surgical problem, with intimal hyperplasia being one of its most important causes. The aim of the present study was to compare in a rabbit model ‘manual’ (hand-sewn) with ‘stapled’ anastomoses (using a staple device) with respect to occurrence and severity of intimal hyperplasia. Materials and Methods: Twenty-four male rabbits (mean weight 2,849 g) were randomly allocated to one of two groups (n = 12). An end-to-end anastomosis of the left femoral artery was performed in all animals under general anesthesia. The anastomosis was hand sewn in group 1, while a vascular closure stapler (VCS) was used in group 2. Both anastomotic time and total operation time were recorded. After 28 days, the rabbits were sacrificed. The femoral artery of operated and nonoperated sides were removed and prepared for anatomopathological examination. The I/M ratio (= difference between tunica intima and tunica media) was determined on hematoxylin-eosin stained slides. All results were analyzed using Student’s t test. Results: Mean anastomotic times were 25 ± 7 min for the ‘manual’ group and 17 ± 9 min for the ‘stapled’ group (p = 0.02). There was no significant difference in the total operation time (55 ± 15 vs. 41 ± 18 min, p = 0.057). All animals survived the anastomosis procedure. In the group of ‘manual’ anastomosis, morbidity was significantly higher. At the moment of sacrifice, all anastomoses were patent. There was no difference in the I/M ratio between the groups. Conclusions: The use of VCS is a promising alternative to hand-sewn anastomoses. It takes less time to perform a stapled anastomosis, the technique has a shorter learning period and morbidity seems to be lower when vascular anastomoses are applied with the VCS in this rabbit model.