Graft Restenosis Research Articles

Coronary arteries bypass grafting stenosis

Article type Review article Coronary artery disease (CAD) is a major global problem. In addition, it is higher risk of mortality for women more than men are when develop in female gender Atherosclerotic plaques consist of deposits of fatty material in the tunica intima. The role of inflammatory process in CAD has been known from 1980's. Several studies investigated the innate immunity and adaptive immunity roles in atherosclerosis and they concluded that it plays a key role in atherosclerosis. Coronary artery bypass grafting (CABG) is a widely used method for the treatment of CAD. Based on the literature, CABG is the most common surgical operation done worldwide. In During the first 10 years after CABG, up to 50% of saphenous grafts will occlude. Graft restenosis is beginning with acute thrombosis, intima hyperplasia, and plaque formation. In this review, some molecular pathways of graft failure and restenosis such as apoptosis and nuclear factor kappa B (NF-ĸB) are described.

Rupture iatrogène intrastent d’un pontage aorto-coronaire veineux traitée avec succès par endoprothèse couverte

Percutaneous coronary interventions of saphenous vein grafts are associated with an increased risk of periprocedural complications; among these, the rupture of the vein graft is probably the less common and the most dangerous; it is even more exceptional when it occurs on a stented portion of the graft. We report the case of a 75-year-old man who presented during a balloon angioplasty of intent restenosis of a saphenous vein graft a spectacular graft rupture at the level of the previously stented site and who was ultimately successfully treated with a covered stent.

Endovascular Therapy is Effective Treatment for Focal Stenoses in Failing Infrapopliteal Vein Grafts

To evaluate the efficacy of endovascular therapy for maintaining patency and preserving limbs among patients with failing infrapopliteal bypass grafts. We gathered data from a registry of catheter-based procedures for peripheral artery disease. Of 1554 arteriograms performed from 2006 to 2012, 30 patients had interventions for failing bypass vein grafts to infrapopliteal target vessels. The first intervention for each patient was used in this analysis. Duplex ultrasonography was used within 30 days after intervention and subsequently at 3- to 6-month intervals for graft surveillance. Interventions were performed for duplex ultrasonography surveillance findings in 21 patients and for symptoms of persistent or recurrent critical limb ischemia in 9 patients. Procedural techniques included cutting balloon angioplasty (83%), conventional balloon angioplasty (7%), and stent placement (10%). Procedural success was achieved in all cases. There were no procedure-related complications, amputations, or deaths within 30 days. By Kaplan-Meier analysis, 37% of the patients were free from graft restenosis at 12 months and 31% were at 24 months. Receiver-operating characteristic analysis indicated that a lesion length of 1.75 cm best predicted freedom from restenosis (C statistic: 0.74). Residual stenosis (P = 0.03), patency without reintervention (P = 0.01), and assisted patency with secondary intervention (P = 0.02) rates were superior for short lesions compared with long lesions. The cohort had acceptable rates of adverse clinical outcomes, with 96% of patients free from amputation at both 12 and 24 months; clinical outcomes were also better in patients with short lesions. In this single-center experience with endovascular therapies to treat failing infrapopliteal bypass grafts, rates of limb preservation were high, but the majority of patients developed graft restenosis within 12 months. Grafts with longer stenoses fared poorly by comparison. These data suggest that endovascular interventions to restore or prolong graft patency may be associated with maintained graft patency and that close follow-up with vascular laboratory surveillance is essential.

A novel agent with histone deacetylase inhibitory activity attenuates neointimal hyperplasia.

Neointimal hyperplasia (NIH), a pathophysiological event identified in bypass graft and stent re-stenosis, is characterised by aberrant vascular smooth muscle cell (VSMC) migration and proliferation. Recent evidence identifies histone deacetylase modulation as a regulator of VSMC proliferation and migration and a potential therapeutic target in the treatment of NIH. The purpose of our study was to determine the in vitro and in vivo potential of a novel agent, MCT-3, to modulate VSMC migration, proliferation and NIH. In vitro VSMC studies utilized reverse transcriptase and real time Q-PCR gene expression analysis, western blot, elisa assay and cellular proliferation and migration scratch assay's. In vivo studies utilized the partial carotid artery ligation model of NIH together with immunohistochemistry in FVB/N mice. MCT-3 treatment induced histone H3 and H4 acetylation and inhibited VSMC migration and proliferation in vitro and significantly attenuated NIH in vivo. MCT-3-mediated regulation of orphan nuclear receptor NUR77, Plasminogen Activator Inhibitor Type-1 (PAI-1) and cyclin dependent kinase inhibitors (CDKI) p21(CIP1/WAF1) and p27(KIP1) expression was also identified. Together these observations identify a novel agent, MCT-3, with histone deacetylase inhibitory activity, able to inhibit NIH and identify a potential molecular mechanism responsible for these effects. Additional pre-clinical studies may be warranted to determine the potential clinical utility of this compound.

γ-Secretase inhibitor DAPT attenuates intimal hyperplasia of vein grafts by inhibition of Notch1 signaling

The proliferation and high plasticity of vascular smooth muscle cells (vSMCs) are the major reasons for restenosis of vein grafts. N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), specific inhibitor of γ-secretase, has been shown to regulate vSMC proliferation and differentiation through the Notch signaling pathway, but the pathophysiological importance of these findings in venous grafts has not yet been determined. A rat vein graft model was employed wherein the left jugular vein was surgically interposed into the left common carotid artery. Daily subcutaneous injections of DAPT or placebo (DMSO) were administered postoperatively (control animals received no treatment). We showed that DAPT can inhibit restenosis of vein grafts by inhibiting vSMC proliferation and increasing apoptosis in vivo. Notch1 signaling was highly active during the development of intima thickening. By blocking the Notch signaling pathway, the γ-secretase inhibitor DAPT can significantly attenuated intima thickening. These changes in vein grafts coincided with enhanced binding of myocardin to the smooth muscle-specific protein SM22 and smooth muscle myosin heavy chain at the promoters of vSMC differentiation-specific genes. These studies showed that DAPT can restore the vSMC phenotype and inhibit vSMC proliferation through suppression of the Notch1 signaling pathway, and thus opens a new avenue for the treatment of restenosis in vein grafts.

Abstract 165: cAMP-Phosphodiesterase 1C Regulates Neointimal Hyperplasia by Controlling Platelet-Derived Growth Factor Receptor ß Degradation via the Endosome-Lysosome Pathway

Neointimal hyperplasia is associated with the development of diverse vascular diseases such as atherosclerosis, vein bypass graft disease and restenosis after percutaneous coronary interventions. Vascular injury-mediated neointimal hyperplasia involves the phenotypic modulation, migration and proliferation of vascular smooth muscle cells (VSMCs). Cyclic nucleotide is vital in regulating VSMC migration and proliferation, which are controlled by cyclic nucleotide phosphodiesterase (PDE) isozymes. To identify the regulation and function of PDEs in VSMC pathogenesis of vascular diseases, we performed systematic screening for all 22 known PDE genes in normal contractile VSMCs and proliferating synthetic VSMCs. Interestingly, we observed that expression of PDE1C was very low in normal contractile VSMCs but drastically elevated in synthetic VSMCs in vitro as well as in vivo in various mouse models of vascular injuries, including carotid artery ligation, femoral artery wire injury and vein bypass graft. Consistently, PDE1C is also highly induced in VSMCs in neointimal lesion of human coronary artery. More importantly, injury-induced neointimal formation was significantly attenuated in pde1c-deficient mice or by perivascular administration of PDE1 inhibitor. Furthermore, PDE1 inhibition also reduced the spontaneous vascular remodeling of human saphenous vein explant in an ex vivo culture model. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of PDGF receptor beta (PDGFR-β). We found that PDE1C knockdown or inhibition markedly decreased the levels of PDGFR-β protein but not mRNA, which was blocked by endosome and lysosome inhibitors. Furthermore, PDE1C inhibition is capable of promoting PDGFR-β internalization and attenuating PDGFR-β membrane accumulation. Finally, we found that PDE1C co-localized with PDGFR-β on cell membrane, which was able to regulate PDGFR-β protein degradation through modulating a transmembrane adenylyl cyclase-cAMP-PKA signaling. Taken together, our present data demonstrated that PDE1C plays a critical role in regulating VSMC proliferation and neointimal hyperplasia, in part, through promoting endosome/lysosome dependent PDGFR-β protein degradation.

Maladapted Endothelial Cells Flip the Mesenchymal Switch

Endothelial cells in the neointima undergo a transition to the mesenchymal phenotype, suggesting a therapeutic target for vein graft restenosis (Cooley et al., this issue).

Optical coherence tomography imaging of intrastent neointimal bridge caused by semicircumferencial dissection after drug eluting balloon dilatation of instent restenosis of sapheneous venous graft

Optical coherence tomography imaging of intrastent neointimal bridge caused by semicircumferencial dissection after drug eluting balloon dilatation of instent restenosis of sapheneous venous graft

Polymer-based delivering of shRNA to rabbit aortic smooth muscle cells suppressed the expression of IGF-1R <italic>in vitro</italic> and <italic>in vivo</italic>

Restenosis is one of clinical limitations for vein graft in coronary bypass graft. It has been proved that signal pathway IGF-1 and its receptor (IGF-1R) activated by hemodynamic mechanical stretch are responsible for the vascular smooth muscle cells proliferation in vein graft neointima formation. Unfortunately, there is no routinely successful method to resolve this problem. Gene delivering to vein graft possesses great therapeutic potential to prevent neointima formation. Polymer is one kind of nanoparticles, which can activate the process of endocytosis of cells. In this study, we evaluated the transfection efficiency and therapeutic potential of polymer-based transfection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) to smooth muscle cells and rabbit external jugular vein graft. Results showed that polymer-based transfection provided high efficiency of transgene expression in smooth muscle cells in vitro. In vitro, IGF-1R-specific shRNA transfected by polymer inhibited IGF-1R protein expression by 52 ± 3.6%, when compared with mock transfected cells. In vivo delivering efficiency of pGFPshIGF-1R plasmid into the rabbit external jugular vein graft was significantly high in the polymer-based transfection group, when compared with negative control group. In vivo, polymer-based transfection IGF-1R-specific shRNA efficiently inhibited the expression of IGF-1R protein by 77 ± 3.6%, 65.6 ± 4.9%, and 76.7 ± 4.3% at 24, 48, and 72 h, respectively, when compared with negative control group. Our findings indicated that polymer-based transfection may be a promising technique that allows the targeting of gene therapy for vein graft restenosis.

Intravascular brachytherapy for peripheral vascular disease

Interventional treatment of arteries that are narrowed and obstructed by atherosclerosis involves either bypassing the blockage using a graft; widening the artery from the inside with a balloon, a procedure known as percutaneous transluminal angioplasty (PTA); or providing a strut to hold the vessel open, known as a stent. All of these treatments are, however, limited by the high numbers that fail within a year. Intravascular brachytherapy is the application of radiation directly to the site of vessel narrowing. It is known to inhibit the processes that lead to restenosis (narrowing) of vessels and grafts after treatment. This is an update of a review first published in 2002. To assess the efficacy of, and complications associated with, intravascular brachytherapy (IVBT) for maintaining patency after angioplasty or stent insertion in native vessels or bypass grafts of the iliac or infrainguinal arteries. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched August 2013) and CENTRAL (2013, Issue 7). Randomised controlled trials of the use of brachytherapy as an adjunct to the endovascular treatment of people with peripheral arterial disease (PAD) or stenosed bypass grafts of the iliac or infrainguinal arteries versus the procedure without brachytherapy. Two review authors independently assessed trial quality and two other review authors independently extracted the data. Adverse event information was collected from the trials. Eight trials with a combined total of 1090 participants were included in this review. All included studies used the femoropopliteal artery. We did not identify any studies that used the iliac arteries. All studies compared PTA with or without stenting plus IVBT versus PTA with or without stenting alone. No trials were found comparing IVBT to technologies such as drug eluting stents or balloons, or cryoplasty. Follow-up ranged from six months to five years. The quality of the included trials was moderate with our concerns relating to the difficulty of blinding due to the nature of the procedures and the small sample sizes for some studies. Primary outcomes (patency or restenosis and need for re-intervention) were reported in the majority of the trials, but reporting at various time points and the use of multiple definitions of the outcomes by the included studies meant that not all data were available for pooling. The secondary outcomes were not reported in many of the included studies.For brachytherapy, cumulative patency was higher at 24 months (odds ratio (OR) 2.36, 95% confidence interval (CI) 1.36 to 4.10, n = 222, P = 0.002). A statistically significant difference was found for restenosis at six months (OR 0.27, 95% CI 0.11 to 0.66, n = 562, P = 0.004), 12 months (OR 0.44, 95% CI 0.28 to 0.68, n = 375, P = 0.0002) and 24 months (OR 0.41, 95% CI 0.21 to 0.78, n = 164, P = 0.007) in favour of IVBT. No difference was found after five years as measured in one study. The need for re-interventions was reported in six studies. Target lesion revascularisation was significantly reduced in trial participants treated with IVBT compared with angioplasty alone (OR 0.51, 95% CI 0.27 to 0.97, P = 0.04) at six months after the interventions. No statistically significant difference was found between the procedures on the need for re-intervention at 12 and 24 months after the procedures.A statistically significant lower number of occlusions was found in the control group at more than three months (OR 11.46, 95% CI 1.44 to 90.96, n = 363, P = 0.02) but no differences were found at less than one month nor at 12 months after the procedures making the clinical significance uncertain. Ankle brachial index was statistically significantly better for IVBT at the 12 month follow-up (mean difference 0.08, 95% CI 0.02 to 0.14, n = 100, P = 0.02) but no statistically significant differences were found at 24 hours and at six months.Quality of life, complications, limb loss, cardiovascular deaths, death from all causes, pain free walking distance and maximum walking distance on a treadmill were similar for the two arms of the trials with no statistically significant difference found between the treatment groups. The evidence for using peripheral artery brachytherapy as an adjunct to percutaneous transluminal angioplasty to maintain patency and for the prevention of restenosis in people with peripheral vascular disease is limited, mainly due to the inconsistency of assessment and reporting of clinically relevant outcomes. More data are needed on clinically relevant outcomes such as health related quality of life (HRQOL) or limb salvage and longer-term outcomes, together with comparisons with other techniques such as drug eluting balloons and stents. Adequately powered randomised controlled trials, health economics and cost-effectiveness data are required before the procedure could be recommended for widespread use.

Overexpression of the growth arrest-specific homeobox gene Gax inhibits proliferation, migration, cell cycle progression, and apoptosis in serum-induced vascular smooth muscle cells.

The Gax gene has been implicated in a variety of cell-developmental and biological processes, and aberrant Gax expression is linked to many diseases. In this study, to provide important insights for Gax-based gene therapy in vein graft restenosis and its anti-restenotic mechanism, we used rabbit vascular smooth muscle cells (VSMCs) to investigate the effects of Gax overexpression on proliferation, migration, cell cycle, and apoptosis in a serum-stimulated culture. Rabbit VSMC lines that stably overexpressed Gax were established by transfection with recombinant adenoviral vector Ad5-Gax. The effect of Gax overexpression on in vitro serum-induced VSMCs proliferation, migration, cell cycle, and apoptosis was assessed by MTT, wound healing, and flow cytometry assays, respectively. To investigate the effect of Gax overexpression on PCNA and MMP-2 in serum-induced VSMCs, immunocytochemistry, RT-PCR, and gelatin zymography were performed. The results clearly showed that Gax overexpression decreases PCNA expression in serum-induced VSMCs. Gax overexpression also significantly inhibited cell proliferation by blocking entry into the S-phase of the cell cycle, promoted cell apoptosis, and reduced cell migration activity by downregulating MMP-2 release and activity. These findings indicate that Gax would be an optimal target gene for gene therapy to treat vein graft restenosis.

G-protein coupled receptor 35 activation mediates human vascular smooth muscle migration

Introduction: GPR35 is a poorly characterised G protein-coupled receptor endogenously activated by kynurenic acid and selectively coupled to Gα13, a G protein involved in regulation of cellular motility and proliferation via the Rho kinase pathway. The role of GPR35 in cardiovascular disease (CVD) is poorly explored, though it has been proposed to regulate blood pressure in rodents. Ligands which activate GPR35 are orthologue selective however, we have identified potent novel human GPR35 specific ligands; agonist pamoic acid and antagonists, CID-2745687 and ML145 for further dissection of GPR35 pharmacology. Based on GPR35's coupling to Gα13, here we investigated the role of GPR35 in primary human saphenous vein vascular smooth muscle cell (HSVSMC) migration and proliferation; a pathological process integral to the development of vein graft failure and restenosis. Methods: Human selective GPR35 ligands were pharmacologically characterised in β-arrestin translocation assays via bioluminenscence resonence energy transfer (BRET) in cells stably expressing FLAG-hGPR35-eYFP (Flp-In TREx 293). Endogenous expression of GPR35 was quantified in HSVSMC via QRT-PCR and migration was measured in HSVSMCs stimulated with 10-500nM pamoic acid, +/- CID-2745687 and ML145 (100nM) or ROCK1/2 inhibitor Y-27632 (10μM) in scratch wound assays using ImageJ. HSVSMC proliferation was assessed via MTS assay. Changes in HSVSMC morphology and actin-cytoskeletal structure were assessed via tetramethyl rhodamine isothiocyanate (TRITC) actin phalloidin staining. Results: BRET assays in FLAG-hGPR35-eYFP cells demonstrated that pamoic acid was a potent, human selective GPR35 agonist (pEC50 7.28±0.007) while CID-2745687 (pIC50 7.16±0.12) and ML145 (pIC50 8.08±0.12) were potent antagonists. QRT-PCR demonstrated HSVSMC endogenously express GPR35 (ΔCT=19.97±0.23, normalised to 18s). Analysis of the actin cytoskeleton revealed GPR35 activation induced a rearrangement of actin filaments consistent with HSVSMC migration. Quantification of HSVSMC migration revealed the GPR35 agonist pamoic acid induced a 30% increase in migration (p 0.05 vs -serum control). GPR35 activation did not affect HSVSMC proliferation. Conclusion: Here, we have described a novel role for GPR35 activation in the migratory capacity of HSVSMC via its downstream effector ROCK1/2. This suggests GPR35 might be a therapeutic target in the setting of vein graft failure and restenosis.

ECM-related gene expression profile in vascular smooth muscle cells from human saphenous vein and internal thoracic artery

Currently, Saphenous vein (SV) and internal thoracic artery (ITA) are still the most common graft materials in Coronary Artery Bypass Grafting (CABG) whereas SV graft have a lower long-term patency than ITA. Vascular smooth muscle cells (VSMCs) phenotype conversion, proliferation and migration may play a key role in mechanism of vein graft restenosis. To explore differential gene expression profile in VSMCs from SV and ITA will help to further elucidate the mechanism of VSMCs in vein graft restenosis after CABG and to provide new thread of gene therapy.MethodsVSMCs from paired SV and ITA were cultured for experiments of Affymetrix microarrays and verification using FQ RT-PCR, while the database for annotation, visualization and integrated discovery bioinformatics resources (DAVID 2.0) was utilized for bioinformatics analysis of differential gene expression profile between SV VSMCs and ITA VSMCs. RNA of tunica media from SV and ITA segments were extracted for FQ RT-PCR to display differential expression of PLATResults54,613 probe sets were examined by gene microarray experiments. In SV VSMCs, 1,075 genes were up-regulated and 406 of them were higher than two-fold; 1,399 genes were down-regulated and 424 of them were lower than two-fold as compare with ITA VSMCs.14 ECM-related genes differentially expressed were verificated and listed as following: COL4A4, COL11A1, FN1, TNC, THBS, FBLN, MMP3, MMP9, TIMP3, WNT5A, SGCD were higher whereas COL14A1, ELN, PLAT lower in SV VSMCs than ITA VSMCs. In addition, PLAT was lower in tunica media from SV segments than ITA.ConclusionVSMCs from SV and ITA have distinct phenotypes characteristics. Both promoting and inhibiting migration ECM-related genes were higher in VSMCs from SV as compared with ITA, suggesting that VSMCs from SV have more potential migrating capability whereas less PLAT both in SV VSMCs and vascular tissue,implying that SV may prone to be restenosis after CABG.

Abstract 509: Inhibition of Patched-1 prevents Injury-induced Neointimal Hyperplasia

Intimal remodeling occurs due to alterations in vascular smooth muscle cell (VSMC) proliferation and apoptosis and is a key event in the pathogenesis of vascular disease. Atherosclerosis, vascular rejection, venous graft restenosis and coronary intervention are each characterized by increased VSMC growth and intimal thickening. Objectives To determine the role of Ptc-1 in mediating pulsatile flow-induced changes in SMC growth and neointimal hyperplasia. Methods and Results HCASMC were exposed to “normal“ or pathological “low” pulsatile flow conditions for 24 h by utilizing a perfused transcapillary flow system. In vivo, pathological low flow conditions following carotid artery ligation increased medial SMC growth while increasing Ptc-1/Notch expression. Inhibition of Ptc-1 expression by cyclopamine attenuated low flow-induced increases in VEGF/Notch expression while concomitantly decreasing HCASMC growth to normal flow levels. Perivascular delivery of Ptc-1 siRNA by pluronic gel inhibited the low flow-induced increases in Ptc-1/Notch expression and subsequent increase in medial SMC growth. In addition, low pulsatile flow-induced increases in neointimal hyperplasia and subsequent decreased lumen volume were returned to sham-operated control levels following ptc-1 gene knockdown. Conclusion These results suggest that pathological low flow stimulates SMC growth and neointimal hyperplasia via Ptc-1 regulation of VEGF/Notch signaling.

Gene Therapy for Vein Graft Failure

The main pathologenesis of vein graft restenosis is neointimal hyperplasia associated with vascular smooth muscle cell migration and proliferation. Gene therapy offers a novel treatment method for reducing or delaying early thrombosis, intimal hyperplasia, and late atherosclerosis. In this review, we will (1) describe sequential pathologies of vein graft disease; (2) summarize the applications of gene therapy in vein graft restenosis; and (3) discuss novel gene therapy for vein graft failure.

Coronary aspirate TNFα reflects saphenous vein bypass graft restenosis risk in diabetic patients

BackgroundPatients with diabetes mellitus (DM) have an increased risk for periprocedural complications and adverse cardiac events after percutaneous coronary intervention. We addressed the potential for coronary microvascular obstruction and restenosis in patients with and without DM undergoing stenting for saphenous vein bypass graft (SVG) stenosis under protection with a distal occlusion/aspiration device.MethodsSVG plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Percent diameter stenosis was determined from quantitative coronary angiography before, immediately after and 6 months after stent implantation. Coronary aspirate was retrieved during stent implantation and divided into particulate debris and plasma. Total calcium, several vasoconstrictors, and tumor necrosis factor (TNF)α in particulate debris and coronary aspirate plasma were determined.ResultsPatients with and without DM had similar plaque volume, but larger necrotic core and greater particulate debris release in patients with than without DM (20.3±2.7 vs. 12.7±2.6% and 143.9±19.3 vs. 75.1±10.4 mg, P<0.05). The TNFα concentration in particulate debris and coronary aspirate plasma was higher in patients with than without DM (15.9±6.6 vs. 5.1±2.4 pmol/mg and 2.2±0.7 vs. 1.1±0.2 pmol/L, P<0.05), whereas total calcium and vasoconstrictors were not different. Patients with DM had a greater percent diameter stenosis 6 months after stent implantation than those without DM (22.17±5.22 vs. 6.34±1.11%, P<0.05). The increase in TNFα immediately after stent implantation correlated with restenosis 6 months later (r=0.69, P<0.05).ConclusionIn diabetics, particulate debris and coronary aspirate plasma contained more TNFα, which might reflect the activity of the underlying atherosclerotic process.Trial registrationURL: http://www.clinicaltrials.gov/ct2/results?term=NCT01430884; unique identifier: NCT01430884

Statins and Infrainguinal Vascular Bypass Procedures

Statins exert several beneficial effects on patients with peripheral arterial disease, whether managed conservatively or undergoing open surgical/endovascular procedures. Statins improve perioperative and long-term mortality and morbidity rates in these patients. There is also evidence that statins improve infrainguinal bypass graft patency rates and are associated with reduced graft restenosis and amputation rates in these procedures. This review considers the beneficial effects of statins on patients undergoing infrainguinal bypass graft procedures and discusses the implicated pathomechanisms.

Early growth response protein 1 promotes restenosis by upregulating intercellular adhesion molecule-1 in vein graft.

Objectives. To verify the relationship between Egr-1 and vein graft restenosis and investigate the related mechanisms. Methods. Mouse vein graft models were established in Egr-1 knockout (KO) and wild-type (WT) mice. The vein grafts in the mice were taken for pathological examination and immunohistochemical analysis. The endothelial cells (ECs) were stimulated by using a computer-controlled cyclic stress unit. BrdU staining and PCR were used to detect ECs proliferation activity and Egr-1 and ICAM-1 mRNA expression, respectively. Western-blot analysis was also used to detect expression of Egr-1 and intercellular adhesion molecule-1 (ICAM-1) proteins. Results. The lumens of vein grafts in Egr-1 KO mice were wider than in WT mice. ECs proliferation after mechanical stretch stimulation was suppressed by Egr-1 knockout (P < 0.05). Both in vein grafts and ECs from WT mice after mechanical stretch stimulation, mRNA expression and protein of Egr-1 and ICAM-1 showed increases (P < 0.05). However, ICAM-1 expression was significantly suppressed in ECs from Egr-1 knockout mice (P < 0.05). Conclusions. Egr-1 may promote ECs proliferation and result in vein graft restenosis by upregulating the expression of ICAM-1. As a key factor of vein graft restenosis, it could be a target for the prevention of restenosis after CABG surgery.

Targeted Treatments for Restenosis and Vein Graft Disease

Surgery to restore blood flow in arteries blocked by atherosclerotic plaque is a common treatment in cardiovascular disease. Long-term complications of surgical treatment are vein graft disease and restenosis, a renarrowing of the blood vessel after bypass or removal of the culprit atherosclerotic plaque. Attempts to prevent or treat these complications by systemic pharmacological approaches have been largely unsuccessful in the clinic. This has led to an interest in developing targeted or locally delivered strategies. This paper discusses many of the various site-delivered therapies that are under examination as potential antirestenotic and antivein graft disease agents (including antithrombotic, antiproliferative, and anti-inflammatory agents) and why many therapies developed in animal models fail in clinical trials. Techniques of targeted delivery (including stents, “magic bullets,” and adventitial delivery) and delivery systems (including nanoparticles and the use of gene therapy) are also discussed.

Statins and Infrainguinal Vascular Bypass Procedures

Statins exert several beneficial effects on patients with peripheral arterial disease, whether managed conservatively or undergoing open surgical/endovascular procedures. Statins improve perioperative and long-term mortality and morbidity rates in these patients. There is also evidence that statins improve infrainguinal bypass graft patency rates and are associated with reduced graft restenosis and amputation rates in these procedures. This review considers the beneficial effects of statins on patients undergoing infrainguinal bypass graft procedures and discusses the implicated pathomechanisms.