Postoperative Intimal Hyperplasia Research Articles

Postoperative Intimal Hyperplasia: Review from My Research

AbstractPostoperative intimal hyperplasia is the major cause of the vein graft occlusion. It is very important to establish an animal model for the start of research. After my vascular surgery residency in Japan, I started my research work on postoperative intimal hyperplasia at the University of Wisconsin-Madison. My research showed that endothelial injury and monocyte infiltration is the key for postoperative intimal hyperplasia, which is very similar to Ross' pathogenesis of atherosclerosis as an inflammatory disease. Focusing on postoperative intimal hyperplasia as an inflammatory disease, especially on tumor necrosis factor-α, FR-167653 (tumor necrosis factor-α suppressive agent, inhibitor of p38 mitogen-activated protein kinase; Fujisawa Pharmaceutical Co., Ltd., Japan) is found to suppress postoperative intimal hyperplasia in a rat model by reducing serum monocyte chemoattractant protein-1 levels. However, FR-167653 is not commercially available today. Because endothelial injury is the first step of postoperative intimal hyperplasia, I investigated whether the free radical scavenger, edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan), which alleviates the endothelial injury in vitro, can also suppress postoperative intimal hyperplasia. Moreover, the free radical scavenger edaravone (Radicut®, Mitsubishi Tanabe Pharma Co.) is also found to suppress postoperative intimal hyperplasia, by alleviating endothelial injury. In clinical settings, it is very important to detect postoperative intimal hyperplasia before its establishment. Hepatocyte growth factor is not only a hepatic growth factor but also a vascular endothelial growth factor. Recently, serum hepatocyte growth factor level was found to be a candidate biomarker for postoperative intimal hyperplasia in our rat model.

Progress in the application of patch materials in cardiovascular surgery.

The cardiovascular patch, served as artificial graft materials to replace heart or vascular tissue defect, is still playing a key role in cardiovascular surgeries. The defects of traditional cardiovascular patch materials may determine its unsatisfactory long-term effect or fatal complications after surgery. Recent studies on many new materials (such as tissue engineered materials, three-dimensional printed materials, etc) are being developed. Patch materials have been widely used in clinical procedures of cardiovascular surgeries such as angioplasty, cardiac atrioventricular wall or atrioventricular septum repair, and valve replacement. The clinical demand for better cardiovascular patch materials is still urgent. However, the cardiovascular patch materials need to adapt to normal coagulation mechanism and durability, promote short-term endothelialization after surgery, and inhibit long-term postoperative intimal hyperplasia, its research and development process is relatively complicated. Understanding the characteristics of various cardiovascular patch materials and their application in cardiovascular surgeries is important for the selection of new clinical surgical materials and the development of cardiovascular patch materials.

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.

An adventitial painting modality of local drug delivery to abate intimal hyperplasia

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. Here we developed a new modality of directly “painting” drug-loaded unimolecular micelles (UM) to the adventitia thus obviating the need for a hydrogel.To render tissue adhesion, we generated amine-reactive unimolecular micelles with N-hydroxysuccinimide ester (UM-NHS) terminal groups to form stable amide bonds with the adventitia. To test periadventitial application, we either soaked balloon-injured rat carotid arteries in crosslinked UM-NHS (Mode-1) or non-crosslinked UM-NHS (Mode-2), or painted the vessel surface with non-crosslinked UM-NHS (Mode-3). The UM-NHS were loaded with or without a model drug (rapamycin) known to be IH inhibitory. We found that Mode-1 produced a marked IH-mitigating drug effect but also caused severe tissue damage. Mode-2 resulted in lower tissue toxicity yet less drug effect on IH. However, the painting method, Mode-3, demonstrated a pronounced therapeutic effect (75% inhibition of IH) without obvious toxicity.In summary, we present a simple painting modality of periadventitial local drug delivery using tissue-adhesive UM. Given the robust IH-abating efficacy and low tissue toxicity, this prototype merits further development towards an effective anti-stenosis therapy suitable for open vascular reconstructions.

Serum Hepatocyte Growth Factor Level as the Biomarker for Postoperative Intimal Hyperplasia

Postoperative intimal hyperplasia is still the major cause of the vein graft occlusion. It may be useful to find the biomarker for the progression of postoperative intimal hyperplasia. The endothelial injury is considered as the first step for postoperative intimal hyperplasia. Hepatocyte growth factor (HGF) is not only the organ specific growth actor, but also the vascular endothelial growth factor. Edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan) is not only the first free radical scavenger commercially available, but also alleviates the endothelial injury in vivo. In this study, we evaluated whether serum HGF levels can be the biomarker for postoperative intimal hyperplasia in the rat model. Moreover, we estimated whether edaravone can suppress postoperative intimal hyperplasia. In the 17 male rats (mean weight 498 ± 53 g), we interposed the right epigastric vein graft into the common femoral artery with 10-0 interrupted sutures, as previously described. The rats were divided into two groups: the Edaravone group, which received preoperative administration of edaravone (3.0 mg/kg) into peritoneal cavity; and the control group, which received the same dose of saline. Vein grafts from each group were stained with hematoxylin and eosin and Elastica Verhoeff’s van Gieson’s. Three unoperated right epigastric veins were also examined a Shame. The initial areas of vein graft were measured using computerized planimetry (NIH Image Ver. 1.61). Serum HGF levels were also measured and compared (unpaired t-test). This study was approved by the Hyogo College of Medicine Animal Research Committee (No. 235). The average of intimal area in Group Control were gradually increased (30 ± 16 × 10-3 mm2 at 2 weeks and 434 ±111 × 10-3 mm2 at 4 weeks), which were significantly suppressed in the Edaravone group (53 ± 54 × 10-3 mm2 at 4 weeks; P < .01). Serum HGF levels were also gradually increased (4.94 ± 0.50 ng/mL at 2 weeks and 7.20 ±1.40 ng/mL at 4 weeks), comparing with that of Shame (3.96 ± 0.22 ng/mL; P < .05) (Figure). Serum HGF levels in the Edaravone group at 4 weeks seemed to be suppressed, but not be significantly when compared with the Control group (5.46 ± 0.55 ng/mL; P = .20) (Fig). Serum HGF levels might be the biomarker for postoperative intimal hyperplasia in the rat model, which can be suppressed with edaravone.

Vascularization of the arteriovenous fistula wall and association with maturation outcomes.

The venous vasa vasorum is the mesh of microvessels that provide oxygen and nutrients to the walls of large veins. Whether changes to the vasa vasorum have any effects on human arteriovenous fistula outcomes remains undetermined. In this study, we challenged the hypothesis that inadequate vascularization of the arteriovenous fistula wall is associated with maturation failure. This case-control pilot study includes pre-access veins and arteriovenous fistula venous samples (i.e. tissue pairs) from 30 patients undergoing two-stage arteriovenous fistula creation (15 matured and 15 failed to mature). Using anti-CD31 immunohistochemistry, we quantified vasa vasorum density and luminal area (vasa vasorum area) in the intima, media, and adventitia of pre-access veins and fistulas. We evaluated the association of pre-existing and postoperative arteriovenous fistula vascularization with maturation failure and with postoperative morphometry. Vascularization of veins and arteriovenous fistulas was predominantly observed in the outer media and adventitia. Only the size of the microvasculature (vasa vasorum area), but not the number of vessels (vasa vasorum density), increased after arteriovenous fistula creation in the adventitia (median vasa vasorum area 1366 µm2/mm2 (interquartile range 495-2582) in veins versus 3077 µm2/mm2 (1812-5323) in arteriovenous fistulas, p < 0.001), while no changes were observed in the intima and media. Postoperative intimal thickness correlated with lower vascularization of the media (r 0.53, p = 0.003 for vasa vasorum density and r 0.37, p = 0.045 for vasa vasorum area). However, there were no significant differences in pre-existing, postoperative, or longitudinal change in vascularization between arteriovenous fistulas with distinct maturation outcomes. The lack of change in intimal and medial vascularization after arteriovenous fistula creation argues against higher oxygen demand in the inner walls of the fistula during the vein to arteriovenous fistula transformation. Postoperative intimal hyperplasia in the arteriovenous fistula wall appears to thrive under hypoxic conditions. Vasa vasorum density and area by themselves are not predictive of maturation outcomes.

The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment.

The molecular mechanism of hemodialysis access arteriovenous fistula (AVF) failure due to venous neointimal hyperplasia (VNH) is not known. The role of microRNA-21 (miR-21) in VNH associated with AVF failure was investigated by performing in vivo and in vitro experiments. In situ hybridization results revealed that miR-21 expression increased and was associated with fibroblasts in failed AVFs from patients. In a murine AVF model, qRT-PCR gene expression results showed a significant increase in miR-21 and a decrease in miR-21 target genes in graft veins (GVs) compared to contralateral veins in mouse AVF. miR-21 knockdown in GVs was performed using a lentivirus-mediated small hairpin RNA (shRNA), and this improved AVF patency with a decrease in neointima compared to control GVs. Moreover, loss of miR-21 in GVs significantly decreased the Tgfβ1, Col-Ia, and Col-Iva genes. Immunohistochemistry demonstrated a significant decrease in myofibroblasts and proliferation with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in miR-21-knockdown vessels, along with a decrease in hypoxia-inducible factor-1 alpha (HIF-1α) and phospho-SMAD2 (pSMAD-2) and phospho-SMAD3 (pSMAD-3) and an increase in phosphatase and tensin homolog (PTEN) staining. Hypoxic fibroblast knockdown for miR-21 showed a significant decrease in Tgfβ-1 expression and pSMAD-2 and -3 levels and a decrease in myofibroblasts. These results indicate that miR-21 upregulation causes VNH formation by fibroblast-to-myofibroblast differentiation.

Transcriptomics of Human Arteriovenous Fistula Failure: Genes Associated With Nonmaturation

Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relieson extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. Case-control study. 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. RNA expression in native veins and AVFs. Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter≥ 6mm. Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate< 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r=0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. Small sample size, analysis of only upper-arm veins and transposed fistulas. Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.

Association of Serum SorLA with Intimal Hyperplasia after Carotid Endarterectomy Operation: A Retrospective Analysis

To study the relevance between serum sorting protein-related receptor containing the low-density lipoprotein receptor class A (SorLA) and intimal hyperplasia (IH) after carotid endarterectomy (CEA) operation. Seventy-nine carotid artery stenosis patients receiving CEA operation from September 2013 to March 2015 were included. Serum SorLA level was detected by enzyme linked immunosorbent assay method preoperatively. All the 79 patients received regular follow-up to diagnose the IH of target lesions, postoperatively. Based on the follow-up data, the patients were divided into IH group (n=10) and non-IH group (n=69). Serum SorLA levels were analyzed using t-test. Receiver-operating characteristic curve was applied to determine the value of serum SorLA to predict the occurrence of IH after CEA operation. Patients in severe IH group had a higher level of serum SorLA than patients in non-IH group (1.648±0.246ng/mL vs. 1.278±0.281ng/mL, P<0.001). When 1.44ng/mL was designated as the cutoff value of serum SorLA, the predicting value had a sensitivity of 90% and a specificity of 73.5%. High serum SorLA level is related to IH after CEA operation. A serum SorLA level of 1.44ng/mL can be used as a predicting index of postoperative IH.

Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.

Similar degree of intimal hyperplasia in surgically detected stenotic and nonstenotic arteriovenous fistula segments: a preliminary report

BackgroundIntimal hyperplasia has been historically associated with improper venous remodeling and stenosis after creation of an arteriovenous fistula. Recently, however, we showed that intimal hyperplasia by itself does not explain the failure of maturation of 2-stage arteriovenous fistulas. We seek to evaluate whether intimal hyperplasia plays a role in the development of focal stenosis of an arteriovenous fistula. MethodsThis study compares intimal hyperplasia lesions in stenotic and nearby nonstenotic segments collected from the same arteriovenous fistula. Focal areas of stenosis were detected in the operating room in patients (n = 14) undergoing the second-stage vein transposition procedure. The entire vein was inspected, and areas of stenosis were visually located with the aid of manual palpation and hemodynamic changes in the vein peripheral and central to the narrowing. Stenotic and nonstenotic segments were documented by photography before tissue collection (14 tissue pairs). Intimal area and thickness, intima-media thickness, and intima to media area ratio were measured in hematoxylin and eosin stained cross-sections followed by pairwise statistical comparisons. ResultsThe intimal area in stenotic and nonstenotic segments ranged from 1.25 to 11.61 mm2 and 1.29 to 5.81 mm2, respectively. There was no significant difference between these 2 groups (P = .26). Maximal intimal thickness (P = .22), maximal intima-media thickness (P = .13), and intima to media area ratio (P = .73) were also similar between both types of segments. ConclusionThis preliminary study indicates that postoperative intimal hyperplasia by itself is not associated with the development of focal venous stenosis in 2-stage fistulas.

Invited commentary

Resolvins are members of a new category of inflammation-reducing mediators derived from omega-3-fatty acids such as those found in certain fish. These lipid compounds were initially identified in inflammatory exudates and have a wide range of modulating effects. Prior investigations have demonstrated their ability to decrease polymorphonuclear recruitment and limit ischemia-reperfusion damage, neovascularization, and release of inflammatory cytokines from macrophages.1Recchiuti A. Resolvin D1 and its GPCRs in resolution circuits of inflammation.Prostaglandins Other Lipid Mediat. 2013; 107: 64-76Crossref PubMed Scopus (35) Google Scholar Innovative studies from Dr Conte's group2Akagi D. Chen M. Toy R. Chatterjee A. Conte M.S. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice.FASEB J. 2015; 29: 2504-2513Crossref PubMed Scopus (77) Google Scholar, 3Miyahara T. Runge S. Chatterjee A. Chen M. Mottola G. Fitzgerald J.M. et al.D-series resolvin attenuates vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury.FASEB. 2013; 27: 2220-2232Crossref PubMed Scopus (98) Google Scholar has previously shown that systemic administration of such specialized proresolving lipid mediators is capable of multiple beneficial effects after arterial injury, including reducing smooth muscle cell responses, decreasing superoxide production and proinflammatory gene expression, and decreasing neointimal hyperplasia. In this report, Wu et al extend their findings to the rat carotid angioplasty model and introduced a novel method for periadventitial delivery. They show that by locally delivering resolvin D1 via thin biodegradable poly(lactic-co-glycolic acid) wraps, it is possible to reduce neointima formation by >50%. Importantly, the authors note minimal toxicity of the compound at the doses used, and this will be of interest for future clinical application. Such findings nicely demonstrate the potential of direct treatment methods to improve patency after open surgical procedures. Several questions remain before full transition to the clinics can begin. The optimal dose and method of delivery will need to be determined, and the need for sustained release vs single application strategies will require definition. Because one of its primary mechanisms involves decreasing inflammatory cell infiltrate, the potential for inhibitory effects on wound healing and infection will need to be investigated. Nevertheless, such promising findings support continued efforts to overcome the frustrating obstacle of postoperative intimal hyperplasia so that we can improve long-term outcomes in our vascular patients. Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injuryJournal of Vascular SurgeryVol. 65Issue 1PreviewLipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury. Full-Text PDF Open Archive

Pre-existing and Postoperative Intimal Hyperplasia and Arteriovenous Fistula Outcomes

The contribution of intimal hyperplasia (IH) to arteriovenous fistula (AVF) failure is uncertain. This observational study assessed the relationship between pre-existing, postoperative, and change in IH over time and AVF outcomes. Prospective cohort study with longitudinal assessment of IH at the time of AVF creation (pre-existing) and transposition (postoperative). Patients were followed up for up to 3.3 years. 96 patients from a single center who underwent AVF surgery initially planned as a 2-stage procedure. Veins and AVF samples were collected from 66 and 86 patients, respectively. Matched-pair tissues were available from 56 of these patients. Pre-existing, postoperative, and change in IH over time. Anatomic maturation failure was defined as an AVF that never reached a diameter > 6mm. Primary unassisted patency was defined as the time elapsed from the second-stage surgery to the first intervention. Maximal intimal thickness in veins and AVFs and change in intimal thickness over time. Pre-existing IH (>0.05mm) was present in 98% of patients. In this group, the median intimal thickness increased 4.40-fold (IQR, 2.17- to 4.94-fold) between AVF creation and transposition. However, this change was not associated with pre-existing thickness (r(2)=0.002; P=0.7). Ten of 96 (10%) AVFs never achieved maturation, whereas 70% of vascular accesses remained patent at the end of the observational period. Postoperative IH was not associated with anatomic maturation failure using univariate logistic regression. Pre-existing, postoperative, and change in IH over time had no effects on primary unassisted patency. The small number of patients from whom longitudinal tissue samples were available and low incidence of anatomic maturation failure, which decreased the statistical power to find associations between end points and IH. Pre-existing, postoperative, and change in IH over time were not associated with 2-stage AVF outcomes.

Suppression of postoperative intimal hyperplasia of vein graft with edaravone in a rat model

Postoperative intimal hyperplasia is still the major cause of vein graft occlusion. No medicine, however, can suppress the development of postoperative intimal hyperplasia. Since June 2001, edaravone has been commercially available as the free radical scavenger for acute cerebral infarction. In addition, it is well known that edaravone in lower dosage also suppresses injury to endothelial cells of vessels in vitro. In this study we evaluated the effect of edaravone on the development of postoperative intimal hyperplasia in a rat model. In ten male rats (498 ± 53 g) we interposed the right epigastric vein graft into the common femoral artery. The ten rats were divided into two groups: edaravone group (n = 5) in which there was the preoperaiive administration of edaravone (3.0 mg/kg) into peritoneal cavity, and the control (n = 5) in which the same dose of saline was used. After 4 weeks three sections were taken from the vein grafts and stained with Verhoeff’s and van Gieson’s stains. The intimal areas of the vein graft were measured using computerized planimetry. The averages of the intimal area and serum monocyte chemoattractant protein 1 (MCP-1) level were compared between the two groups. The mean ischemic time was 68 ± 6 min. The average of the intimal area in the edaravone group was significantly lower than the control group (0.05 ± 0.02 mm2 vs. 0.43 ± 0.05 mm2, p < 0.001). The average of serum MCP-1 in the edaravone group was also significantly lower than that of the control group (116 ± 11 pg/mL. vs. 169 ± 10 pg/mL, p < 0.01). Our results suggested that edaravone could suppress postoperative intimal hyperplasia of the vein graft in a rat model.

Edaravone suppresses endothelial cell injury in vein grafts of a rat model

Postoperative intimal hyperplasia, the major cause of vein graft occlusion, is initiated by endothelial injury. Using a high-magnification scanning electron microscope (SEM), the surfaces of endothelial cells in vein grafts were examined to investigate the protective mechanism of the free radical scavenger edaravone (Radicut, Mitsubishi Tanabe Pharma Co, Japan) against endothelial injury in postoperative intimal hyperplasia. In 10 male Lewis rats with a mean (± SD) weight of 495±28 g, a right epigastric vein graft was interposed into the common femoral artery. Five rats received preoperative intraperitoneal administration of edaravone (3.0 mg/kg; edaravone group). The other five received an equal volume of saline preoperatively (sham operation group). Unoperated right epigastric veins were also examined as controls. The vein grafts from each group were examined using an S-800 Hitachi SEM (Hitachi High-Technologies Co, Japan) at ×10,000 to ×20,000 magnification. Unoperated endothelial cells had smooth surfaces. While endothelial cells in the sham operation group had very rough surfaces with platelet adhesion, endothelial cells in the edaravone group had smooth surfaces without platelet adhesion, very similar to unoperated endothelial cells. These SEM results showed that edaravone may maintain the smooth surface of endothelial cells. The authors postulate that edaravone suppresses postoperative intimal hyperplasia by alleviating endothelial injury.

The Effects of Toradol on Postoperative Intimal Hyperplasia in a Rat Carotid Endarterectomy Model: Laboratory Research

Carotid endarterectomy (CEA) and more recently carotid artery stenting are the treatments of choice for atherosclerotic disease of the extracranial carotid arteries; however, early restenosis caused by neointimal hyperplasia confounds surgical therapy. Oxidative stress has been implicated in the progression of intimal hyperplasia. The authors hypothesized that ketorolac tromethamine (Toradol), a nonsteroidal antiinflammatory drug that is a potent cyclooxygenase inhibitor, would decrease oxidative stress and thereby reduce intimal hyperplasia in a rat CEA model. Twenty-nine male Sprague-Dawley rats underwent CEA and were divided into 3 treatment groups as follows: (1) control (placebo), (2) 7.5 mg/kg Toradol, and (3) 10 mg/kg Toradol. Toradol treatment began 2 days before CEA and continued for 2 weeks. Two weeks after endarterectomy, carotid arteries were fixed, harvested, and examined for platelet activity (platelet reactive units), oxidative stress (malondialdehyde and glutathione), and intimal hyperplasia (measured as percentage of luminal stenosis). Platelet activity, malondialdehyde and glutathione, and intimal hyperplasia were all significantly lowered in both 7.5- and 10-mg/kg doses of Toradol versus control. Toradol given daily beginning 2 days before CEA and ending 2 weeks after the procedure was effective at significantly reducing platelet activity, oxidative stress, and intimal hyperplasia development in the rat without any increase in bleeding. Although the mechanism of action of this reduction is not completely understood, one possible explanation may be through the inhibition of reactive oxygen species production.

Suppression of postoperative intimal hyperplasia of vein grafts with edaravone in rat models - a scanning electron microscope study.

Postoperative intimal hyperplasia, the most common cause of vein graft occlusion, is initiated by endothelial injury. In the present study, the mechanism by which the free radical scavenger edaravone (Radicut, Mitsubishi Tanabe Pharma Co, Japan) protects against endothelial injury in postoperative intimal hyperplasia was investigated. In 18 male Lewis rats, a right epigastric vein graft was interposed into the common femoral artery. Nine rats received a pre-operative intraperitoneal administration of edaravone (3.0 mg/kg, edaravone group) and the other nine rats received an equal volume of saline (saline group). After 1 h, five vein grafts from each group were treated with Verhoeff-van Gieson elastica stain and subjected to a histological examination. The other four vein grafts from each group were examined with an S-800 Hitachi scanning electron microscope (SEM) (Hitachi High-Technologies Co, Japan) at ×1000 magnification, as were three unoperated right epigastric veins (unoperated vein group). The endothelial areas of the vein grafts were measured using computerized planimetry of the SEM images (ImageJ version 1.37, National Institutes of Health, USA). The mean endothelial areas (%) were compared between the two groups. Verhoeff-van Gieson elastica stain revealed no significant differences between the two groups. SEM showed that endothelial cells in the unoperated epigastric vein had a cobblestone-like appearance. In the saline group, the endothelial cells were comb-shaped and had adherent monocytes. In the edaravone group, however, the cobblestone-like appearance of endothelial cells was well preserved, with little monocyte adhesion. Moreover, the mean (± standard error of the mean) endothelial area was significantly higher in vein grafts from the edaravone group than in those from the saline group (74±1.8% versus 56±4.3%, P<0.05), and was similar to those in the unoperated epigastric veins (72±1.9%). These findings show that endothelial injury is present soon after placement of the interposition graft. The authors believe that edaravone suppresses postoperative intimal hyperplasia by alleviating endothelial injury.

Numerical study of hemodynamics comparison between small and large femoral bypass grafts

AbstractThe geometry factors have prominent impacts on the flow patterns of bypass graft. In order to clarify the influence of graft diameter on the hemodynamics of femoral bypass graft, the pulsatile blood flows in three bypassing models with different graft diameters were simulated with finite‐element method. The temporal–spatial distributions of flow patterns, pressure drops, and wall shear stresses were depicted and compared. The results indicated that femoral artery bypassed with a large graft demonstrates relatively better and more profitable hemodynamic phenomena with large longitudinal velocity, uniform wall shear stress, and small wall shear stress gradient. The large model may be effective in decreasing the probability of the initiation and development of postoperative intimal hyperplasia and restenosis. Copyright © 2007 John Wiley &amp; Sons, Ltd.

Suppression of postoperative intimal hyperplasia of vein graft with edaravone in a rat model

Postoperative intimal hyperplasia is still the major cause of vein graft occlusion. No medicine, however, can suppress the development of postoperative intimal hyperplasia. Since June 2001, edaravone has been commercially available as the free radical scavenger for acute cerebral infarction. In addition, it is well known that edaravone in lower dosage also suppresses injury to endothelial cells of vessels in vitro. In this study we evaluated the effect of edaravone on the development of postoperative intimal hyperplasia in a rat model. In ten male rats (498 ± 53 g) we interposed the right epigastric vein graft into the common femoral artery. The ten rats were divided into two groups: edaravone group (n = 5) in which there was the preoperaiive administration of edaravone (3.0 mg/kg) into peritoneal cavity, and the control (n = 5) in which the same dose of saline was used. After 4 weeks three sections were taken from the vein grafts and stained with Verhoeff's and van Gieson's stains. The intimal areas of the vein graft were measured using computerized planimetry. The averages of the intimal area and serum monocyte chemoattractant protein 1 (MCP-1) level were compared between the two groups. The mean ischemic time was 68 ± 6 min. The average of the intimal area in the edaravone group was significantly lower than the control group (0.05 ± 0.02 mm2 vs. 0.43 ± 0.05 mm2, p < 0.001). The average of serum MCP-1 in the edaravone group was also significantly lower than that of the control group (116 ± 11 pg/mL. vs. 169 ± 10 pg/mL, p < 0.01). Our results suggested that edaravone could suppress postoperative intimal hyperplasia of the vein graft in a rat model.

Wall shear stresses in small and large two-way bypass grafts

Wall shear stress, as one of the most important hemodynamic parameters of the cardiovascular system, has been studied extensively in the numerical and experimental approaches to blood flow in various arteries. In order to clarify the influence of graft diameter on the wall shear stress in a femoral two-way bypass graft, the pulsatile blood flows in two models were simulated with the finite element method. Both models were constructed with different diameters of grafts. The main geometric structure and the boundary conditions were identical for both models. The emphasis was on the comparison analysis of wall shear stresses in the vicinity of the distal anastomosis. The temporal–spatial distributions of wall shear stresses, wall shear stress gradients, and oscillating shear index were analyzed and compared. The present study indicated that femoral artery bypassed with a large graft demonstrated relatively uniform wall shear stresses and small wall shear stress gradients, whereas it does not have advantages in the oscillating shear index. The large model exhibits better and more regular hemodynamic phenomena and may be effective in decreasing the probability of the initiation and development of postoperative intimal hyperplasia and restenosis. Thus, appropriately large grafts are applicable in the clinical practice of femoral two-way bypass operation. More detailed studies are necessary on this problem for the purpose of increasing the success rates of the femoral bypass grafts.