Degree Of Intimal Hyperplasia Research Articles

Management of failed flow diversion for intracranial aneurysm beyond the first 6 months of follow-up: an international Delphi consensus.

The placement of flow-diverting devices has become a common method of treating unruptured intracranial aneurysms of the internal carotid artery. The progressive improvement of aneurysm occlusion after treatment-with low complication and rupture rates-has led to a dilemma regarding the management of aneurysms in which occlusion has not occurred within 6-24 months. The authors aimed to identify clinical consensus regarding management of intracranial aneurysms displaying persistent filling 6-24 months after flow diversion and to ascertain questions that may drive future investigation. An international panel of 67 experts was invited to participate in a multistep Delphi consensus process on the treatment of intracranial aneurysms after failed flow diversion. Of the 67 experts invited, 23 (34%) participated. Qualitative analysis of an initial survey with open-ended questions resulted in 51 statements regarding management of aneurysms showing persistent filling after flow diversion. The statements were grouped into 8 categories, and in the second round, respondents rated the degree of their agreement with each statement on a 5-point Likert scale. Flow diverters with surface modifiers did not influence administration of dual-antiplatelet therapy according to 83%. Consensus was also reached regarding the definition of treatment failure at specific time points, including at 6 months if there is aneurysm growth or persistent rapid flow through the entirety of the aneurysm (96%), at 12 months if there is aneurysm growth or symptom onset (78%), and at 24 months if there is persistent filling regardless of size and filling characteristics (74%). Although experts agreed that the degree of intimal hyperplasia or in-device stenosis could not be ascertained by noninvasive imaging alone (83%), only 65% chose digital subtraction angiography as the preferred modality. At 6 and 12 months, retreatment is preferred if there is persistent filling with aneurysm growth (96%, 96%), device malposition (48%, 87%), or a history of subarachnoid hemorrhage (65%, 70%), respectively, and at 24 months if there is persistent filling without reduction in aneurysm size (74%). Experts favored treatment with an additional flow diverter (87%) over aneurysm clipping, applying the same principles for follow-up (83%) and treatment failure (91%) as for the first flow diverter. The authors present the consensus practices of experts in the management of intracranial aneurysms without occlusion 6-24 months after treatment with a flow-diverting device.

Saphenous vein graft longevity: open or endoscopic, with VEST or without?

We have read the article by Sandner et al. with great interest. The authors have undertaken a post hoc analysis of the VEST III Trial to examine the impact of open versus endoscopic harvesting techniques on saphenous vein graft patency and degree of intimal hyperplasia. As already acknowledged by the authors, these results should be viewed as hypothesis generating because of the inherent limitations of a post hoc, unplanned analysis. The key findings of the paper point towards a better saphenous vein graft patency and reduced intimal hyperplasia of open harvest technique compared to endoscopic harvest. The reduced graft patency associated with endoscopic harvest has already been suggested in the literature [1], and this could be related to several factors. Endoscopic vein harvest is a relatively newly established technique where graft patency is influenced by the operator experience, something that has not been accounted for in the VEST III trial. Other factors intrinsic to the endoscopic harvest technique that result in poorer patency include the thermal diathermy injury of the conduit or more traumatic handling/stretch of the conduit that translates into histological evidence of trauma [2]. A strength of the paper is the within-patient randomized that mitigated the potential effect of variability in saphenous vein preparation on graft patency. For example, an open no-touch technique or the distending pressure used on the vein for leaks check are known determinants of angiographic graft patency [3] and graft wall remodelling [4].

Ginsenoside Rg1 prevents vascular intimal hyperplasia involved by SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in a rat balloon injury

Ethnopharmacological relevancePanax ginseng C. A. Mey. is a traditional tonic that has been used for thousands of years, and has positive effects on vascular diseases. Ginsenoside Rg1 (GS-Rg1) is one of the active ingredients of Panax ginseng C. A. Mey. and has been shown to have beneficial effects against ischemia/reperfusion injury. Our previously study has found that GS-Rg1 can mobilize bone marrow stem cells and inhibit vascular smooth muscle proliferation and phenotype transformation. However, pharmacological effects and mechanism of GS-Rg1 in inhibiting intimal hyperplasia is still unknown. Aim of the studyThis study was aimed to investigate whether GS-Rg1 prevented vascular intimal hyperplasia, and the involvement of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1 axes. Materials and methodsRats were operated with carotid artery balloon injury. The treatment groups were injected with 4, 8 and 16 mg/kg of GS-Rg1 for 14 days. The degree of intimal hyperplasia was evaluated by histopathological examination. The expression of α-SMA (α-smooth muscle actin) and CD133 were detected by double-label immunofluorescence. Serum levels of SDF-1α, SCF and soluble FKN (sFKN) were detected by enzyme linked immunosorbent assay (ELISA). The protein expressions of SCF, SDF-1α and FKN, as well as the receptors c-kit, CXC chemokine receptor type 4 (CXCR4) and CX3C chemokine receptor type 1 (CX3CR1) were detected by immunochemistry. ResultsGS-Rg1 reduced intimal hyperplasia by evidence of the values of NIA, the ratio of NIA/MA, and the ratio of NIA/IELA and the ratio of NIA/LA, especially in 16 mg/kg group. Furthermore, GS-Rg1 8 mg/kg group and 16 mg/kg group decreased the protein expressions of the SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in neointima, meanwhile GS-Rg1 8 mg/kg group and 16 mg/kg group also attenuated the expressions of SDF-1α, SCF and sFKN in serum. In addition, the expression of α-SMA and CD133 marked smooth muscle progenitor cells (SMPCs) was decreased after GS-Rg1 treatment. ConclusionsGS-Rg1 has a positive effect on inhibiting vascular intimal hyperplasia, and the underlying mechanism is related to inhibitory expression of SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes.

Effects of Systemic and Local Caffeine on Vessel Diameter, Anastomosis Patency, and Intimal Hyperplasia in the Rat.

The use of caffeine is not recommended prior to elective microsurgery due to its demonstrated negative effects on vessel anastomosis by the presumed sympathomimetic induction of vasoconstriction. In this study, we aimed to elucidate the systemic and local effects of caffeine on vessel diameter, anastomosis patency, and degree of intimal hyperplasia during the healing process. Twenty-five rats were randomly assigned to five groups: (1) negative control, (2) preoperative systemic caffeine, (3) postoperative systemic caffeine, (4) perioperative systemic caffeine, and (5) a local caffeine group. Both the right and left femoral arteries were used. Ten anastomoses were performed per group. The arterial diameter was measured by micrometer, anastomosis patency was assessed surgically and histologically, and the histological examination was conducted 3 weeks postoperatively to determine intimal hyperplasia. The overall patency rate was 96%. Mild vasoconstriction was observed in the systemic caffeine groups (statistically insignificant); however, there were no negative effects on anastomosis patency. Local caffeine irrigation resulted in significant vasodilatation in the local caffeine group (p = 0.001); a similar effect was not observed in the other groups. There was a significant decrease in the intima/media ratio in the local caffeine group (p < 0.01), when compared with the control and systemic caffeine groups. No other intima/media ratio differences were observed among other comparison groups. The systemic administration of caffeine, although statistically insignificant, has an observable effect on vasoconstriction. However, it does not appear to have negative effects on anastomosis patency regardless of its application period (pre-, post-, or perioperatively). The local application of caffeine resulted in considerable vasodilatation as opposed to the vasoconstriction effect in the systemic caffeine groups. Decreased intimal hyperplasia at the anastomosis edge, and antifibrotic properties in the surgical field were also observed in this group. Histologically, the local caffeine group demonstrated an additional beneficial effect on anastomosis remodeling.

Kindlin-2 siRNA inhibits vascular smooth muscle cell proliferation, migration and intimal hyperplasia via Wnt signaling.

It is known that vascular smooth muscle cell (VSMC) proliferation and migration leads to intimal hyperplasia in cases of atherosclerosis and restenosis. In the present study, we investigated the effects of kindlin-2 on VSMC proliferation, migration and intimal hyperplasia, and the underlying mechanisms. The left common carotid artery of Sprague‑Dawley rats were subjected to balloon injury in order to induce intimal hyperplasia, and then transfected with kindlin-2 small interfering RNA (siRNA) lentivirus or negative control siRNA lentivirus. We noted that the degree of intimal hyperplasia 4 weeks after balloon injury was significantly reduced in arteries transfected with kindlin-2 siRNA lentivirus (P<0.05). In vitro, kindlin-2 siRNA suppressed VSMC proliferation and migration induced by Wnt3a (100 ng/ml). Western blot analyses and RT-qPCR revealed that kindlin-2 regulated Wnt/β-catenin signaling and thereby modulated the expression of β-catenin target genes, including c-myc and cyclin D1. This study demonstrated that kindlin-2 plays a critical role in VSMC proliferation, migration and intimal hyperplasia via Wnt signaling. Therefore, blocking the activity of kindlin-2 represents a novel therapeutic strategy for vascular injury.

The physiologic and histologic properties of the distal internal thoracic artery and its subdivisions

We compared the flow rates, reactivity, and morphology of the distal internal thoracic artery and its branches, the superior epigastric and musculophrenic arteries, to test their applicability as possible conduits in coronary artery bypass grafting surgeries. Skeletonized internal thoracic artery and subdivisions of patients undergoing coronary artery bypass grafting were studied intraoperatively (n = 100) for flow and length measurements and in vitro in organ baths (n = 58) for active response to norepinephrine. Quantitative microscopic analysis of the muscle density and degree of intimal hyperplasia was performed. Results were analyzed according to age, gender, risk factors, and medications. Internal thoracic artery subdivisions contributed an average extra length of 2 cm. Free flow rates were 129 ± 45 mL/min, 114 ± 41 mL/min, and 93 ± 36 mL/min in the internal thoracic artery, superior epigastric artery, and musculophrenic artery, respectively. Sternum and internal thoracic artery length and free flow rates were significantly lower in women. The subdivisions were significantly more reactive to norepinephrine than the distal internal thoracic artery (P ∼ .005), although sensitivity to norepinephrine was similar. Patients treated with beta-blockers had significantly decreased reactivity (P = .009). Microscopic analysis suggests similar muscle content in the internal thoracic artery and subdivisions. Eccentric (28%) and concentric (62%) intimal hyperplasia were observed in 90% of specimens, with no evidence for atherosclerotic plaques. There was no significant difference in the degree of intimal hyperplasia between the distal internal thoracic artery and its subdivisions, and there was no correlation to risk factors. Our results confirm the previous studies on the higher contractility in internal thoracic artery subdivisions, suggesting caution in the use of the bifurcation for revascularization. However, the extra length, sufficient flow, and favorable histologic properties suggest that the bifurcation may be appropriate for coronary revascularization in selected cases.

The performance of a small-calibre graft for vascular reconstructions in a senescent sheep model

There is an acute clinical need for small-calibre (<6 mm) vascular grafts for surgery. The aim of this study was to evaluate the long-term performance of a small-calibre graft produced from a nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(carbonate-urea)urethane (POSS-PCU), in a large animal model following Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) protocols. Grafts were characterised and implanted into the left carotid artery (LCA) of senescent sheep (n = 11) for a period of 9 months. In vivo compliance and blood flow rates were measured using ultrasound wall tracking software and a Transonic flow meter. Graft patency and degree of intimal hyperplasia (IH) were examined at the study end point. Seven of the POSS-PCU grafts were free from thrombosis, IH, calcification and aneurysmal dilation, with 4 occluding within 14 days. All of the ePTFE controls (n = 4) were found to be occluded by day 32. The lumen of the patent POSS-PCU grafts was free from any cellular deposits, whilst perigraft tissue could be seen to be infiltrating into the body of the graft from the adventitia. No significant differences were detected between the blood flow rates (p = 0.3693) and compliance (p = 0.9706) of the POSS-PCU grafts and the native artery, either post-operatively or after 9 months implantation. Small-calibre vascular grafts produced from POSS-PCU offer a viable option for the clinical use in revascularisation procedures with a patency rate of 64%.

Possible Involvement of Altered Arginase Activity, Arginase Type I and Type II Expressions, and Nitric Oxide Production in Occurrence of Intimal Hyperplasia in Premenopausal Human Uterine Arteries

In the present experiments, we tried to elucidate whether changes in arginase activity and protein expression of arginase I and II are involved in the occurrence of intimal hyperplasia in premenopausal human uterine arteries. They were obtained from thirty-four patients undergoing total abdominal hysterectomy with informed consent for the present study. All specimens were assessed histologically and the intima/media ratio (%) was evaluated as an index of the intimal hyperplasia. Thirteen patients out of 34 had histologically normal arteries (intima/media ratio = 18.1 ± 0.7%), whereas the remaining 21 patients had various degrees of intimal hyperplasia (intima/media ratio = 32.7 ± 2.3%), and these specimens were categorized as hyperplasic. Intimal hyperplasia was accompanied by impaired cyclic GMP production, enhanced overall arginase activity, and up-regulations of arginase I and II in endothelial cells and of arginase II in the smooth muscle layer. Pearson’s correlation coefficient analyses revealed the close relationships among the arginase activities in endothelial cells and smooth muscle layer, the intimal /media ratio, and cyclic GMP production. These results suggest that the enhanced arginase activity and expressions of two arginase subtypes shed new light on the processes associated with the occurrence of intimal hyperplasia in premenopausal human uterine arteries.

Is intimal hyperplasia a marker of neuro-ophthalmic complications of giant cell arteritis?

The ischaemic complications of giant cell arteritis (GCA) such as blindness and stroke may result from luminal narrowing of the affected arteries. This study focuses on the association between the severity of intimal proliferation on temporal artery biopsy (TAB) histology and neuro-ophthalmic complications (NOCs) of GCA. We identified 30 cases of biopsy-proven temporal arteritis. One histopathologist (blinded to the clinical details) evaluated the TAB specimens and categorized the degree of maximum stenosis due to intimal hyperplasia into four grades: grade 1 is <50% luminal occlusion due to intimal hyperplasia, grade 2 is 50-75%, grade 3 is >75% and grade 4 is complete luminal occlusion. A second histopathologist (also blinded to the clinical details) independently evaluated the TAB specimens using the same grading system. The NOCs in these patients were noted after a case record review. Of the 30 patients, 12 had NOC-10 with eye complications (complete visual loss, anterior ischaemic neuropathy, visual field defects), one patient had cerebral infarcts and one had both cerebral infarcts and vision loss. There was evidence for a statistically significant trend of NOC associated with higher intimal hyperplasia scores (P = 0.001). The scores of the histopathologists agreed for 23 (77%) patients and differed by 1 category for the remaining 7 (kappa-statistic 0.88). Our study suggests that the degree of intimal hyperplasia on TAB histology (routinely available to all hospital units) seems to be closely associated with NOCs of GCA. The study highlights the possible prognostic as well as diagnostic role of the biopsy. We feel that intimal hyperplasia noted in biopsy specimens may help us in the risk stratification of GCA patients and targeting of appropriate and novel therapies.

Effect of Olmesartan Medoxomil on Atherosclerosis

Angiotensin II is a potent vasoconstrictor and may also contribute to the progression of atherosclerosis. In atheromatous lesions located in human coronary and carotid arteries, angiotensin-converting enzyme and angiotensin II levels are significantly increased. Angiotensin II is known to have proinflammatory actions in vascular tissues, inducing inflammatory cytokines and oxidative stress. In particular, angiotensin II activates the potent cytoplasmic transcription factor nuclear factor-kappaB, which regulates leukocyte adhesion molecules, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-6, and contributes to the recruitment of circulating mononuclear leukocytes to the arterial intima. Olmesartan medoxomil has one of the highest degrees of antihypertensive efficacy among the angiotensin II type 1 receptor antagonists. In the EUTOPIA (EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis) trial, olmesartan medoxomil significantly reduced serum levels of high-sensitivity C-reactive protein, high-sensitivity TNFalpha, IL-6, and MCP-1, all of which are involved in promoting atherosclerosis. In a monkey atherosclerotic model, a 3-D intravascular ultrasound analysis of aortas showed that serum levels of MCP-1 and the degree of intimal hyperplasia were significantly lower after treatment with olmesartan medoxomil than before treatment. In VIOS (Vascular Improvement with Olmesartan Medoxomil Study), treatment with olmesartan medoxomil for 1 year, significantly reduced the wall-to-lumen ratio in arteries, whereas atenolol did not. Thus, olmesartan medoxomil, which rapidly reduces inflammatory markers, may have a beneficial antiatherosclerotic effect.

Effect of low molecular weight heparin on intimal hyperplasia.

Intimal hyperplasia is a significant cause of vascular graft failure. To investigate the potential uses of low molecular weight heparins (LMWHs) as prophylactic agents against graft thrombosis in humans, the anti-proliferative effects of a regimen of subcutaneous LMWH have been studied in an experimental model. Aortic intimal hyperplasia was created in 30 New Zealand White rabbits by endothelial denudation using an embolectomy balloon catheter technique. Three groups of ten animals were randomized to act as controls or to be treated with subcutaneous LMWH once or twice daily for 4 weeks. At 4 weeks all animals were killed and the aortas were harvested for analysis. The degree of intimal hyperplasia was measured using a computerized image analysis system and was expressed as an intimal:medial area ratio and also as percentage luminal reduction. A 60 per cent reduction in the degree of intimal hyperplasia was seen following treatment with LMWH. Heparin-treated animals had considerably less luminal reduction (daily LMWH 8 per cent and twice-daily LMWH 10 per cent) compared with untreated controls (26 per cent) (P less than 0.001). There was a similar difference seen in the intima:media area ratios, daily LMWH 0.38, and twice-daily LMWH 0.44, versus controls, 1.11 (P less than 0.001). In an experimental model, subcutaneous LMWH therapy effectively inhibits intimal hyperplasia.

Effect of Clopidogrel on Platelet Aggregation and Intimal Hyperplasia following Carotid Endarterectomy in the Rat

Intimal hyperplasia results in significant morbidity and mortality following vascular intervention. Both platelets and elevated homocysteine have been implicated in the development of intimal hyperplasia. We previously demonstrated that a locally applied antiplatelet agent decreases the development of intimal hyperplasia. We were therefore interested in a systemic antiplatelet agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet aggregation and activity and intimal hyperplasia. Male Sprague-Dawley rats underwent carotid endarterectomy (CEA) and treatment with either placebo or varying regimens of clopidogrel, including chronic, pre-CEA bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a homocystine diet was used to elevate both plasma homocysteine and the degree of intimal hyperplasia. Platelet aggregation, platelet activity, and intimal hyperplasia were then assessed. Platelet aggregation was not decreased with chronic clopidogrel; however, it was decreased with pre-CEA bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus, nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a decrease in both platelet aggregation and activity, it was unable to decrease the development of intimal hyperplasia at any dose. Additional factors must therefore contribute to the pathologic development of intimal hyperplasia.

203. Electroporation-Mediated Gene Delivery to Mouse Femoral Arteries in a Model of Vascular Injury

Vascular diseases such as atherosclerosis, restenosis and vein graft stenosis affect millions of Americans each year. The pathophysiologies of these diseases all consist of unregulated smooth muscle cell proliferation that results in intimal hyperplasia and ultimately vascular occlusion. Gene therapy is a promising treatment option for smooth muscle proliferative diseases with several genes identified as potential therapies. However, the efficient delivery of these genes to the target cells remains a major limiting factor. Our lab recently developed a non-viral delivery method for gene transfer to the vasculature using electroporation. We have demonstrated that plasmid delivery by electroporation results in high level gene expression in rat mesenteric arteries with expression peaking between 1 and 3 days post transfer. Based on our results in the mesenteric arteries, we reasoned that electroporation could be used to deliver genes to other vascular beds. Using a square wave electroporator (200 V/cm, 8 pulses of 10msec duration) we delivered GFP and luciferase reporter plasmids to femoral arteries of mice. Delivery of a GFP-expressing plasmid results in expression not unlike that we have previously observed in the mesenteric arteries, and histological analysis was used to determine the localization of gene expression. To quantify the levels of gene expression, we delivered a CMV driven luciferase-expressing plasmid. In animals receiving DNA plus electroporation, we obtained an average of 200 pg/mouse with up to nanogram levels at 2 days post-transfer. In contrast, luciferase expression was undetected in arteries receiving DNA but no electroporation. These levels are similar to those achieved in the mesenteric vessels, thus providing evidence that our previously described gene delivery method for the vasculature can be successfully applied to multiple vascular beds. To extend these findings to a vascular disease model, we have focused on a mouse model of restenosis where a polyethylene cuff placed around the femoral artery results in significant intimal hyperplasia at 21 days post-injury. Based on results from other labs demonstrating that early expression of the cell cycle inhibitor p27 can inhibit intimal hyperplasia following vascular injury, we hypothesized that delivering a p27 expressing plasmid to the mouse femoral artery by electroporation immediately before cuff placement would decrease the degree of intimal thickening after injury, providing protection from intimal hyperplasia and vessel occlusion. To test this hypothesis we delivered a CMV driven p27 expressing plasmid by electroporation, placed the cuff, and assayed the degree of intimal hyperplasia by morphometric analysis on hematoxylin and eosin stained thin sections at 21 days post-injury. As expected, injury was less severe in the treated animals. Taken together with our previous results using a rat carotid angioplasty model, these results suggest that electroporation-mediated gene transfer of cytostatic genes can protect from restenosis.

Intimal hyperplasia in the distal ulnar artery: Influence of gender and implications for the hypothenar hammer syndrome

Introduction The distal ulnar artery in the hand is subjected to trauma when the hypothenar eminence is used as a hammer. The clinical presentation of arterial obstruction or aneurysm formation at this site with a history of trauma to the hypothenar eminence is termed the hypothenar hammer syndrome (HHS) and is most commonly observed in the right hands of men. Since the trauma-inducing activities associated with the HHS are common, the histopathology of this arterial segment in our autopsy population was evaluated. Methods The distal ulnar artery in the hand was examined in 21 randomly selected autopsies. Formalin-fixed paraffin-embedded cross sections of artery were assessed using hematoxylin and eosin (H&E), trichrome and elastic stains as well as immunohistochemistry for CD34 and α-smooth muscle actin. Results Intimal hyperplasia is common at this site in the vasculature. The degree of intimal hyperplasia, as assessed by the intima/media ratio, is significantly greater in the right hands of men than in either their corresponding left hands or in women. None of the arterial segments examined contained foam cells or extracellular lipid deposits indicative of atherosclerosis. Conclusions In the injury-prone segment of the distal ulnar artery, intimal hyperplasia is common but is particularly severe in the right hands of men, correlating with the demographics of the HHS. Although, this arterial segment frequently develops intimal hyperplasia, it is resistant to the development of atherosclerosis.

Superior performance of thrombomodulin coated small caliber ePTFE grafts

Introduction: The performance of synthetic bypass grafts to tibial level outflow arteries is greatly limited by early thrombosis and intimal hyperplasia. In addition to its anticoagulant effect, thrombomodulin (TM), an endogenous thrombin inhibitor, also displays anti-proliferative and anti-migratory effects on vascular smooth muscle cells. In this study, we coated small caliber expanded polytetrafluoroethylene (ePTFE) grafts with TM to examine its effect on patency and intimal hyperplasia. Methods: 4 mm diameter ePTFE grafts were pretreated with the cross-linking agent 1-ethyl-3-(3-diamethylaminopropyl)-carbodiimide and then incubated with either 40μg (0.1 μg/μl) TM or buffer control at 4o C overnight. Either coated or uncoated grafts were then surgically implanted into the common carotid arteries of male pigs (32–47 kg) as an interposition graft. Grafts were then harvested at 1 week post-implantation and analyzed grossly and histologically for patency and intimal hyperplasia. Samples were also analyzed by scanning (SEM) and transmission (TEM) electron microscopy and immunohistochemistry for the presence of TM on the graft surface at explantation. Results: Successful coating of ePTFE with soluble TM was confirmed using SEM and TEM and protein C activation assays prior to implantation. At 1 week following implantation, 5 of 6 uncoated grafts thrombosed while 5 of 6 TM coated grafts remained patent (P = 0.01). In addition, endothelialization was evident histologically on the TM coated grafts and absent in control grafts. No difference was observed in degree of intimal hyperplasia at 1 week with minimal hyperplasia in either group at this early time point. SEM, TEM and immunohistochemical staining demonstrated the presence of TM remaining on the surface of the explanted coated grafts (open circles). Conclusion: Thrombomodulin can be durably coated onto ePTFE with TM remaining on the graft under arterial flow conditions. TM appears to promote endothelial growth and provides an anti-thrombotic surface to reduce early graft thrombosis.

Overexpression of von Willebrand factor is an independent risk factor for pathogenesis of intimal hyperplasia: Preliminary studies

Deposition of von Willebrand factor (vWF) is increased in hyperplastic intima of grafts, vWF levels are elevated in patients with cardiovascular diseases, and there is resistance to progression of atherosclerosis in pigs with von Willebrand disease. We hypothesize that increased expression of endothelial vWF has mitogenic effects on smooth muscle cell (SMC) proliferation. In an in vitro study, mouse aortic smooth muscle cells (SMC) were exposed to vWF in various concentrations (0, 5, 20, 100, 500, and 1000 ng/mL). DNA synthesis of SMC was measured with (3)H-thymidine incorporation. In an in vivo study, 108 mice from inbred strains of C57BL/6J (control) and RIIIS/J (characteristic of low plasma vWF) underwent carotid artery ligation (flow cessation model) and were divided into three groups: C57BL/6J, RIIIS/J, and RIIIS/J treated with desmopressin (DDAVP; intraperitoneal injection at 3 micro g/kg/d). At 2 and 4 weeks, carotid arteries were harvested for analysis with immunohistochemical analysis, morphometric studies, and reverse transcriptase polymerase chain reaction; plasma vWF was measured with an enzyme-linked immunosorbent assay. In vitro SMC proliferation showed a positive dose-response curve with vWF stimulation. Intimal hyperplasia (IH) in carotid arteries was prominent in C57BL/6J mice, absent in RIIIS/J mice, and moderate in RIIIS/J treated with DDAVP (intima-media ratio, 71% +/- 18%, 0, and 32% +/- 12%, respectively; P <.01). vWF deposition occurred in all hyperplastic intima subjacent to intact endothelium. Plasma vWF correlated with degree of IH (110% +/- 10%, 21% +/- 7%, and 45% +/- 8%, respectively; P <.05). vWF-messenger RNA was 9 times higher in carotid arteries of C57BL/6J mice and 4 times higher in RIIIS/J with DDAVP, compared with RIIIS/J. vWF directly stimulates SMC proliferation in vitro via a direct dose-response effect. In vivo low shear stress accelerates IH proportional to vWF expression. This could occur under intact endothelium without platelet activation and platelet-derived growth factor release. In effect, control of IH may entail modulation of vWF expression.

Endogenous Nitric Oxide Synthase Inhibitors in Endothelial Cells, Endothelin-1 Within the Vessel Wall, and Intimal Hyperplasia in Perimenopausal Human Uterine Arteries

The present experiments were designed to investigate the ability to produce nitric oxide, concentrations of N(G)-monomethyl-L-arginine (L-NMMA), and asymmetric N(G), N(G)-dimethyl-L-arginine (ADMA) in endothelial cells, endothelin-1 within the vessel wall, and the degree of intimal hyperplasia (intima/media ratio) in perimenopausal human uterine arteries. According to the tentative classification based on basal cyclic GMP levels, 16 arteries could be grouped into groups I and II consisting of eight each. Net production of the nucleotide was significantly higher in group I than that in group II. Concentration of L-NMMA plus ADMA and endothelin-1 content were significantly higher in group II. All specimens from group I were histologically normal, whereas mild to severe intimal hyperplasia was observed in group II specimens. Although considerable individual variations were detectable in the intima/media ratio, L-NMMA plus ADMA and endothelin-1 (n = 35 each), there were significant and positive correlations between three parameters, indicating that intimal hyperplasia became greater as L-NMMA plus ADMA and endothelin-1 were increased. These results suggest that endogenous nitric oxide synthase inhibitors in endothelial cells and endothelin-1 within the vessel wall are important markers of intimal hyperplasia.

Relation between residual plaque burden after stenting and six-month angiographic restenosis

The degree of residual plaque burden outside of a stent might be correlated with the degree of intimal hyperplasia. However, the relation between residual plaque burden and angiographic restenosis are still unknown in a large number of patients. Therefore, we evaluated the effect of residual plaque burden after stenting on 6-month angiographic restenosis. Intravascular ultrasound (IVUS)-guided coronary stenting was successfully performed in 723 patients with 785 native coronary lesions. Six-month follow-up angiograms and evaluation of residual plaque burden by IVUS were available in 566 patients (78.3%) with 622 lesions (79.2%). Results were evaluated using conventional methods. The overall angiographic restenosis rate was 23.0% (143 of 622 lesions). There was no significant difference in residual plaque burden between the lesions with and without restenosis (52% vs 51%, respectively, p = 0.148). The angiographic restenosis rate was 20.8% (11 of 53 lesions), 21.6% (51 of 236 lesions), 22.0% (55 of 250 lesions), and 31.3% (26 of 83 lesions) in the lesions with residual plaque burden <40%, between 40% and 50%, between 50% and 60%, and >60%, respectively (p = 0.284). Using multivariate logistic regression analysis, the only independent predictor of angiographic restenosis was the IVUS stent area (odds ratio 0.807, 95% confidence intervals 0.69 to 0.95, p = 0.011). Furthermore, even in the lesions with residual plaque burden >60%, the restenosis rate was 37.3% (23 of 61 lesions) versus 13.6% (3 of 22 lesions ) in IVUS stent areas of <7 and ≥7 mm 2, respectively (p = 0.031). In conclusion, residual plaque burden outside the stent might not predict angiographic restenosis. IVUS stent area was the only independent predictor of angiographic restenosis.

Palmaz Stent Deployment for Subclavian and Brachiocephalic Arterial Occlusive Disease

Palmaz stent deployment is a useful method for subclavian and brachiocephalic arterial occlusive disease. We evaluated restenosis or intimal thickening after Palmaz stent deployment for nine lesions of subclavian or brachiocephalic arterial occlusive disease focusing on stent diameter, atheroma thickness near the stent, and degree of coverage for the lesion. Follow up DSA and IVUS at 5-14 months (mean 9) after therapy showed no significant changes in the size or shape of the stent itself There were two lesions of thin in-stent intimal hyperplasia and five lesions of thick hyperplasia. There was no close relationship between intimal hyperplasia and stent diameter or atheroma size (relative thickness). There was some relationship between the degree of coverage of the lesion by the stent and degree of intimal hyperplasia, but to determine statistical significance, accumulation of a greater number of cases is necessary.

Inhibitory effect of prostaglandin E 1 on intimal thickening caused by poor runoff conditions in the canine autologous vein grafts.

The efficacy of ONO-1608, a newly developed liposomal formulation of prostaglandin E 1 prodrug, was evaluated on intimal hyperplasia of experimental canine autologous vein grafts under distal poor runoff conditions. The femoral vein was implanted into the femoral artery, preparing a distal poor runoff canine model. After 4 weeks of preparing the poor runoff model, the femoral vein was implanted into the femoral artery. They were then divided into two groups consisting of the control group and the ONO-1608 group. At 4 weeks, the grafts were harvested and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine incorporation 2 weeks after surgery. In addition, the effect of ONO-1608 on the proliferation of platelet-derived growth factor (PDGF)-stimulated human aortic smooth muscle cells (HASMCs) in culture was also investigated. At 4 weeks, the degree of intimal hyperplasia of the graft in the ONO-1608 group was significantly less than that of the control group. The bromodeoxyuridine labeling index 2 weeks after grafting was significantly lower in the ONO-1608 group compared with that in the control group. In addition, ONO-1608 significantly inhibited the proliferation of PDGF-stimulated HASMCs in culture. These results demonstrate the efficacy of ONO-1608 in reducing the degree of intimal hyperplasia of canine autogenous vein grafts under poor runoff conditions. The mechanism of reducing the intimal hyperplasia may be that ONO-1608 inhibited PDGF-stimulated proliferation of the smooth muscle cell. These results suggest that the administration of ONO-1608 may be beneficial in patients who have undergone gone arterial reconstruction.