Vein Graft Failure Research Articles

Relationship between plaque composition by virtual histology intravascular ultrasound and clinical outcomes after percutaneous coronary intervention in saphenous vein graft disease patients: study protocol of a prospective cohort study

BackgroundPlaque composition and morphologic characteristics identified by virtual histology intravascular ultrasound (VH-IVUS) can determine plaques at increased risk of clinical events following percutaneous coronary intervention (PCI) among coronary artery disease (CAD) patients. However, there have been few studies to investigate the relationship between plaque composition of saphenous vein graft (SVG) by VH-IVUS and clinical outcomes in patients with saphenous vein graft disease (SVGD) undergoing PCI. The purpose of this study is to determine whether plaque components and characteristics by VH-IVUS can predict major adverse cardiac events (MACEs) among SVGD patients undergoing PCI.Methods/designThis is a prospective cohort study conducted in Tianjin Chest Hospital, China. Participants with SVGD referred for PCI will be invited to participate in this study, and will be followed up at 1, 6, 12, 24 and 36 months post-PCI to assess clinical outcomes.The planned sample size is 175 subjects. We will recruit subjects with SVGD scheduled to receive PCI, aged 18–80 years, with a history of previous coronary artery bypass graft (CABG) surgery more than 1 year ago, and willing to participate in the study and sign informed consent.The composite primary study endpoint is the incidence of MACEs after PCI for SVGD, including death from cardiac causes, non-fatal myocardial infarction, unplanned target lesion revascularization (TLR) and target vessel revascularization (TVR). The primary outcome analysis will be presented as Kaplan-Meier estimates and the primary outcome analysis will be carried out using a Cox proportional hazards regression model.DiscussionOnce the predictive values of plaque components and characteristics by VH-IVUS on subsequent clinical outcomes are determined among SVGD patients undergoing PCI, an innovative prediction tool of clinical outcomes for SVGD patients undergoing PCI will be created, which may lead to the development of new methods of risk stratification and intervention guidance.Trial registrationThe study is registered to ClinicalTrials.gov (NCT03175952).

Angiographic appearance of patent saphenous vein grafts more than 25 years after coronary artery bypass grafting.

Nine patients with ten angiographical patent saphenous vein grafts (SVG) more than 25years after coronary artery bypass grafting (CABG) at Kawasaki Medical School Hospital between 1976 and 1992 were reviewed. Patent SVG disease was assessed using the FitzGibbon classification, and clinical characteristics which might affect the longevity of SVG were retrospectively evaluated. The mean duration between surgery and current coronary angiography was approximately 30years (25-35years). There were two perfectly patent SVGs (FitzGibbon AI, 35 and 32years after surgery), both of which were bypass grafts to the left anterior descending arteries (LAD). The other eight grafts exhibited some vein graft disease (BII:3, BIII:5). The sequential anastomosis was performed for 5 SVGs. The SVGs bypassed to the good run-off LAD, sequential bypass, strict medical management including cessation of smoking and body weight control may contribute to the slow progression of vein graft disease after CABG.

Long-term performance of an external stent for saphenous vein grafts: the VEST IV trial

BackgroundExternally stenting saphenous vein grafts reduces intimal hyperplasia, improves lumen uniformity and reduces oscillatory shear stress 1 year following surgery. The present study is the first to present the longer-term (4.5 years) performance and biomechanical effects of externally stented saphenous vein grafts.MethodsThirty patients previously implanted with the VEST external stent in the randomized, within-patient-controlled VEST I study were followed up for adverse events; 21 of these were available to undergo coronary angiography and intravascular ultrasound.ResultsTwenty-one stented and 29 nonstented saphenous vein grafts were evaluated by angiography and ultrasound at 4.5 ± 0.3 years. Vein graft failure rates were comparable between stented and nonstented grafts (30 and 23% respectively; p = 0.42). All failures were apparent at 1 year except for one additional nonstented failure at 4.5 years. In patent vein grafts, Fitzgibbon perfect patency remained significantly higher in the stented versus nonstented vein grafts (81 and 48% respectively, p = 0.002), while intimal hyperplasia area (4.27 mm2 ± 1.27 mm2 and 5.23 mm2 ± 1.83 mm2 respectively, p < 0.001) and thickness (0.36 mm ± 0.09 mm and 0.42 mm ± 0.11 mm respectively, p < 0.001) were significantly reduced. Intimal hyperplasia proliferation correlated with lumen uniformity and with the distance between the stent and the lumen (p = 0.04 and p < 0.001 respectively).ConclusionsExternal stenting mitigates saphenous vein graft remodeling and significantly reduces diffuse intimal hyperplasia and the development of lumen irregularities 4.5 years after coronary artery bypass surgery. Close conformity of the stent to the vessel wall appears to be an important factor.Trial registrationNCT01415245. Registered 11 August 2011.

Vein Graft Disease is Prevented by Toll-like Receptor 3 Via Type-I Interferon Induced Decrease of Inflammatory Responses

Background: Venous grafts, used as conduits to bypass occluded arteries, have low patency levels due to extensive intimal hyperplasia (IH). This study aims to investigate the role of TLR3 and downstream Interferon Regulatory Factors (IRF) 3 and 7, regulators of type-I interferons (IFN) and pro-inflammatory cytokines in vein graft disease. Methods: Tlr3-/-, Irf3-/-, Irf7-/- and control mice (n=7–9/group) underwent vein graft surgery. At t28 immunohistochemical analysis and a RT2-profiler PCR array of TLR-responsive genes were performed. mRNA expression of TLR-responsive genes were measured in vein grafts and TLR3 ligand stimulated bone marrow-derived macrophages (BMM). Statistical analyses on parametric data were performed by using a 2-tailed Student’s t-test to compare individual groups, Mann-Whitney test was used for nonparametric data. Results: PolyI:C stimulated BMM show increased expression of type-I IFN inducible genes Ifit and Mx1, indicating type-I IFN regulation downstream TLR3. Tlr3-/- vein grafts demonstrated 1.8-fold increased IH (p=0.009) and increased macrophage influx (p=0.002) compared to controls. Multiple type-I IFN inducible genes were down-regulated in Tlr3-/- vein grafts. PolyI:C stimulated BMM of Tlr3-/- mice showed reduced Ifit1 (75%, p=0.003) and Mx1 (63%, p<0.0001) expression and increased Ccl2 (56%, p=0.006) and Tnfα (51% p=0.003) expression compared to controls. Irf3-/- and Irf7-/- vein grafts show increased IH (resp. 1.4-fold, p=0.0003 and 1.7-fold, p=0.04) including increased macrophage influx. Ifit1, Ifit3 and Isg15 were down-regulated in vein grafts of both strains. Irf3-/- and Irf7-/- BMM expressed significant lreduced IFNβ whereas only Irf3-/- BMM showed reduced Ccl2 (93%, p=0.007) and Tnfα (68%, p<0.0001) expression compared to control BMM. Conclusion: We here show that TLR3 is protective in vein grafts via downstream IRF3 and IRF7 dependent type-I IFN regulation and IRF3 dependent pro-inflammatory cytokine regulation.

Torsion Does Not Affect Early Vein Graft Patency in the Rat Femoral Artery Model.

Torsion of vein grafts is a commonly cited reason for graft failure in clinical setting. Many microsurgery training courses have incorporated vein graft procedures in their curricula, and vein graft torsion is a common technical error made by the surgeons in these courses. To improve our understanding of the clinical reproducibility of practicing vein graft procedures in microsurgery training courses, this study aims to determine if torsion can lead to early vein graft failure in nonsurvival surgery rat models. Sprague-Dawley rats were divided into five cohorts with five rats per cohort for a total of 25 rats. Cohorts were labeled based on degree of vein graft torsion (0, 45, 90, 135, and 180 degrees). Torsion was created in the vein grafts at the distal arterial end by mismatching sutures placed between the proximal end of the vein graft and the distal arterial end. Vein graft patency was then verified 2 and 24 hours postoperation. All vein grafts were patent 2 and 24 hours postoperation. At 2 hours, the average blood flow rate measurements for 0, 45, 90, 135, and 180 degrees of torsion were 0.37 ± 0.02, 0.38 ± 0.04, 0.34 ± 0.01, 0.33 ± 0.01, and 0.29 ± 0.02 mL/min, respectively. At 24 hours, they were 0.94 ± 0.07, 1.03 ± 0.15, 1.26 ± 0.22, 1.41 ± 0.11, and 0.89 ± 0.15 mL/min, respectively. Torsion of up to 180 degrees does not affect early vein graft patency in rat models. To improve the clinical reproducibility of practicing vein graft procedures in rat models, we suggest that microsurgery instructors assess vein graft torsion prior to clamp release, as vessel torsion does not seem to affect graft patency once the clamps are removed.

Anti-phosphorylcholine IgM, an Anti-inflammatory Mediator, Predicts Peripheral Vein Graft Failure: A Prospective Observational Study

One third of infrainguinal vein bypasses may fail within the first 1.5 years. Pro- and anti-inflammatory mechanisms are thought to be involved in these graft stenoses and occlusions. In previous studies, low levels of anti-phosphorylcholine IgM (anti-PC IgM, an innate anti-inflammatory IgM) have been associated with increased cardiovascular events. In this study, the peri-operative dynamics of anti-PC IgM levels were established during leg bypass surgery, and associations assessed between anti-PC IgM levels and primary graft patency. This was a prospective, observational cohort study of infrainguinal autogenous vein bypass for peripheral arterial occlusive disease involving four university affiliated hospitals. Plasma cytokine and anti-PC IgM levels were measured pre- and post-operatively. The outcome of interest was loss of primary graft patency because of occlusion or intervention for graft stenosis. One hundred and forty-two consecutive patients were enrolled: mean age 66 (46-91); 91% white race and male; 72.5% critical limb ischaemia (Fontaine III or IV). Median pre-operative anti-PC IgM levels were 49 units/mL (IQR 32.3-107.7, mean 89.8+101 sd). During follow up of an average of 1.8 years (1 month-7.4 years), 50 (35.2%) grafts lost primary patency. Pre-operative levels of interleukin 6 or C-reactive protein did not predict graft failure. Patients with pre-operative anti-PC IgM values in the lowest quartile had a twofold increased risk of graft failure (multivariable Cox proportional hazard, p=.03, HR 2.11, 95% CI 1.09-4.07), even after accounting for the other significant factors of conduit diameter, distal anastomosis, smoking, and the severity of leg ischaemia. Low levels of anti-PC IgM are associated with vein bypass graft failure. This biological mediator may be a useful marker to identify patients at higher risk, and offers the potential for novel, directed therapies for vascular inflammation and its consequences.

Relationship between intra-operative vein graft treatment with DuraGraft® or saline and clinical outcomes after coronary artery bypass grafting

ABSTRACTBackground: Saphenous vein grafts (SVGs) remain the most often used conduits for coronary bypass grafting (CABG). Progressive intimal hyperplasia contributes to vein-graft disease and vein-graft failure (VGF). We compared the impact of intraoperative preservation of SVGs in a storage solution (DuraGraft®) versus heparinized saline on VGF-related outcomes after CABG.Methods: From 1996 to 2004, 2436 patients underwent isolated CABG with ≥ 1 SVG. SVGs were consecutively treated with DuraGraft in 1036 patients (2001−2004) and heparinized saline in 1400 patients (1996−1999). Short- (< 30 days) and long-term (≥ 1000 days) outcomes were assessed using repeat revascularization (primary end point), and major adverse cardiac events (MACE) consisting of the composite of death, nonfatal myocardial infarction, or repeat revascularization.Results: Mean follow-up in the DuraGraft group was 8.5 ± 4.2 years and 9.9 ± 5.6 years in controls. Short-term event rates were low and generally did not differ between groups. DuraGraft was associated with a 45% lower occurrence of nonfatal myocardial infarction after 1000 days (hazard ratio 0.55, 95% CI 0.41−0.74; P < 0.0001). There was 35% and 19% lower long-term risk for revascularization (HR 0.65, 95% CI 0.44−0.97; P = 0.037) and MACE (HR 0.81, 95% CI 0.70−0.94; P = 0.0051), respectively, after DuraGraft. Mortality was comparable between both groups at 1, 5, and 10 years. There was no statistically significant association between DuraGraft exposure and time to death starting at 30 or 1000 days (HR 0.91, 95% CI 0.76−1.09; P = 0.29).Conclusion: In this study, intraoperative treatment of SVGs with DuraGraft was associated with a lower risk of long-term adverse events suggesting that efficient intraoperative SVG treatment may reduce VGF-related complications post-CABG. These data warrant randomized clinical trials to validate these findings.

MicroRNA‐146a sponge therapy suppresses neointimal formation in rat vein grafts

The long-term failure of vein grafts due to neointimal hyperplasia remains a difficult problem in cardiovascular surgery. Exploring novel approaches to prevent neointimal hyperplasia is important. MicroRNA-146a (miR-146a) plays an essential role in promoting vascular smooth muscle cell (VSMC) proliferation. Thus, the aim of the present study is to investigate whether adenovirus-mediated miR-146a sponge (Ad-miR-146a-SP) gene therapy could attenuate neointimal formation in rat vein grafts. (Ad-miR-146a-SP) was constructed to transfect cultured VSMCs and grafted veins. To improve the efficiency of transferring the miR-146a sponge gene into the grafted veins, 20% poloxamer F-127 gel incorporated with 0.25% trypsin was used to increase adenovirus contact time and penetration. miR-146a-SP transduction significantly reduced the expression of miR-146a both in cultured VSMCs and vein grafts. miR-146a sponge markedly attenuated VSMC proliferation and migration. Consistent with this, miR-146a sponge gene therapy significantly attenuated neointimal formation and also improved blood flow in the vein grafts. Mechanistically, we identified the Krüppel-like factor 4(KLF4) as a potential downstream target gene of miR-146a in vein grafts. Our data show that miR-146a sponge gene therapy could effectively reduce miR-146a activity and attenuate neointimal formation in vein grafts, suggesting its potential therapeutic application for prevention of vein graft failure. © 2018 IUBMB Life, 71(1):125-133, 2019.

The effect of storage solutions on endothelial function and saphenous vein graft patency.

Vein graft failure is a complex mechanism that can be triggered immediately after surgical harvesting. Storage solutions have a major role in preventing endothelial cell damage during harvesting. While normal saline is still widely used, buffered solutions seem to better preserve endothelial integrity and function. This review aims to summarize the current literature surrounding vein graft storage solutions.

A Rabbit Model of Durable Transgene Expression in Jugular Vein to Common Carotid Artery Interposition Grafts.

Vein graft bypass surgery is a common treatment for occlusive arterial disease; however, long-term success is limited by graft failure due to thrombosis, intimal hyperplasia, and atherosclerosis. The goal of this article is to demonstrate a method for placing bilateral venous interposition grafts in a rabbit, then transducing the grafts with a gene transfer vector that achieves durable transgene expression. The method allows the investigation of the biological roles of genes and their protein products in normal vein graft homeostasis. It also allows the testing of transgenes for the activities that could prevent vein graft failure, e.g., whether the expression of a transgene prevents the neointimal growth, reduces the vascular inflammation, or reduces atherosclerosis in rabbits fed with a high-fat diet. During an initial survival surgery, the segments of right and left external jugular vein are excised and placed bilaterally as reversed end-to-side common carotid artery interposition grafts. During a second survival surgery, performed 28 days later, each of the grafts is isolated from the circulation with vascular clips and the lumens are filled (via an arteriotomy) with a solution containing a helper-dependent adenoviral (HDAd) vector. After a 20-min incubation, the vector solution is aspirated, the arteriotomy is repaired, and flow is restored. The veins are harvested at time points dictated by individual experimental protocols. The 28-day delay between the graft placement and the transduction is necessary to ensure the adaptation of the vein graft to the arterial circulation. This adaptation avoids rapid loss of transgene expression that occurs in vein grafts transduced before or immediately after grafting. The method is unique in its ability to achieve durable, stable transgene expression in grafted veins. Compared to other large animal vein graft models, rabbits have advantages of low cost and easy handling. Compared to rodent vein graft models, rabbits have larger and easier-to-manipulate blood vessels that provide abundant tissue for analysis.

Review of risk factors, treatment, and prevention of saphenous vein graft disease after coronary artery bypass grafting.

Saphenous vein graft disease (SVGD) is a type of vascular disease that may develop after coronary artery bypass grafting (CABG). SVGD seriously affects the short-term and long-term effects of CABG and increases the incidence of major adverse cardiovascular events. It is very important to identify patients at greatest risk and carry out prevention and treatment measures to determine the risk factors for SVGD. Many factors contribute to SVGD when the vein is grafted into an arterial environment, such as surgery-related factors, smoking, diabetes mellitus, hyperlipidemia, and others. In this review, we discuss the risk factors for SVGD, current surgical and pharmacologic therapies with which to manage SVGD, and the prevention of SVGD.

TCT-522 Long-Term Outcomes with Saphenous Vein Graft versus Native Coronary Artery Intervention in Patients with Coronary Artery Bypass Grafting: Evidence From Meta-analysis and Meta-regression

Patients with prior CABG often present with saphenous vein graft (SVG) failure. Outcomes with intervention to SVG vs corresponding native vessel (NV) in those patients remains controversial. We searched online databases for studies reporting outcomes with SVG vs NV PCI in patients with prior CABG.

P3203Transduction of microRNA-145 using poly lactic-co-glycolic acid nanoparticles attenuates venous intimal hyperplasia in a rabbit vein graft disease model

P3203Transduction of microRNA-145 using poly lactic-co-glycolic acid nanoparticles attenuates venous intimal hyperplasia in a rabbit vein graft disease model

Intensive versus moderate statin therapy and early graft occlusion after coronary bypass surgery: The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events randomized clinical trial

ObjectiveStatins prevent saphenous vein graft (SVG) disease and improve outcomes after coronary artery bypass graft surgery. However, the optimal postoperative statin dose remains unclear. The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events trial was undertaken to evaluate whether early postoperative high-dose statin therapy reduces SVG occlusion compared with conventional moderate-dose therapy. MethodsIn this pilot, multicenter, double-blind randomized trial, 173 patients who had coronary artery bypass graft surgery with SVG were randomized to receive 10 mg or 80 mg atorvastatin daily for 1 year. The primary outcome was SVG occlusion at 1 year. Secondary outcomes were SVG stenosis and major adverse cardiovascular events. ResultsDuring trial enrollment, patients randomized to 80 mg atorvastatin achieved significantly lower low-density lipoprotein cholesterol levels (P < .00001). One-year graft assessment was performed in 145 patients (83.8%). The primary outcome, SVG occlusion at 1 year, did not significantly differ between the 2 groups (12.9% vs 11.4% for 10 mg atorvastatin vs 80 mg atorvastatin; P = .85). The incidence of vein graft stenosis also did not significantly differ between the groups (P = .54). However, there was a trend toward fewer patients developing vein graft disease (either occlusion or stenosis) in the 80 mg atorvastatin group (29.2% vs 19.2%, 10 mg atorvastatin vs 80 mg atorvastatin; P = .18). Freedom from major adverse cardiovascular events at 1 year was similar between the groups (P = .27). ConclusionsCompared with 10 mg atorvastatin, 80 mg atorvastatin did not significantly reduce vein graft occlusion 1 year after coronary artery bypass graft surgery in this pilot trial.

Influence of a Novel Morphology-Driven Classification on Limb Salvage After Tibial Intervention for Limb-Threatening Critical Ischemia

Infrapopliteal interventions for limb-threatening critical ischemia can be affected by the morphology of the tibial vessels. The aim of this study was to examine the impact of a novel morphology-driven classification on the outcomes of endovascular intervention for limb-threatening critical ischemia. A database of patients undergoing lower extremity endovascular interventions between 2007 and 2017 was retrospectively queried. Patients with isolated infrapopliteal disease were identified, and their anatomy was scored by lesion calcification, target vessel diameter <3.0 mm, lesion length >300 mm, and poor pedal runoff score. Patients were then divided into three groups with 0 or 1 (low risk), 2 (moderate risk), and 3 or 4 (high risk) factors. Intention-to-treat analysis by patient was performed. Outcomes were then assessed for amputation-free survival and freedom from major adverse limb events (MALEs). Anatomic predictors and risk stratification for MALEs were analyzed by Cox proportional hazard analysis. There were 1334 patients (55% male; average age, 60 years; 2134 vessels) who underwent tibial intervention for limb-threatening critical ischemia. The average Edifoligide for the Prevention of Vein Graft Failure in Lower Extremity Bypass Surgery—Phase III Trial (PREVENT III) amputation risk score (PIII score) was 4.5 ± 1.6 (mean ± standard deviation), with 13% considered high risk overall. Technical success was 96%. Overall major adverse cardiovascular event rate was 3% and MALE rate was 19% at 30 days. Major amputation rate was 11% at 30 days. At 5 years, overall cardiac event rate was 41% ± 4% (mean ± standard error of the mean); overall amputation-free survival, 34% ± 3%; and overall MALE rate, 45% ± 4%. When stratified by morphology, those patients with high-risk morphology had worse short-term and long-term outcomes (Table).TableOutcomes of endovascular tibial intervention stratified by morphologyLow riskModerate riskHigh riskNo. of limbs at risk240507587No. of vessels598918619High-risk PIII score35a8b30-Day MACE12330-Day MALE418a45b30-Day amputation rate81233a5-Year CE, mean ± SEM58 ± 540 ± 6a23 ± 9 b,c5-Year AFS, mean ± SEM55 ± 537 ± 6a18 ± 7b,c5-Year MALE, mean ± SEM60 ± 546 ± 5a22 ± 9b,dAFS, Amputation-free survival; CE, cardiac event; MACE, major adverse cardiovascular event; MALE, major adverse limb event; PIII, Edifoligide for the Prevention of Vein Graft Failure in Lower Extremity Bypass Surgery—Phase III Trial (PREVENT III); SEM, standard error of the mean.Values are reported as percentage unless otherwise indicated.aP < .05 compared with low risk.bP < .01 compared with low risk.cP < .05 compared with moderate risk.dP < .01 compared with moderate risk. Open table in a new tab AFS, Amputation-free survival; CE, cardiac event; MACE, major adverse cardiovascular event; MALE, major adverse limb event; PIII, Edifoligide for the Prevention of Vein Graft Failure in Lower Extremity Bypass Surgery—Phase III Trial (PREVENT III); SEM, standard error of the mean. Values are reported as percentage unless otherwise indicated. aP < .05 compared with low risk. bP < .01 compared with low risk. cP < .05 compared with moderate risk. dP < .01 compared with moderate risk. Anatomic morphology affects isolated endovascular tibial intervention, with adverse morphology associated with poorer short- and long-term outcomes. Risk stratification based on anatomic predictors should be considered as one intervenes on infrapopliteal vessels for limb-threatening critical ischemia.

Association between proprotein convertase subtilisin/kexin type 9 and late saphenous vein graft disease after coronary artery bypass grafting: a cross-sectional study

ObjectiveThe study aims to explore the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) level and saphenous vein grafts disease (SVGD) after coronary artery bypass grafting (CABG).DesignA cross-sectional study.SettingA...

The protective role of Toll-like receptor 3 and type-I interferons in the pathophysiology of vein graft disease

BackgroundVenous grafts are commonly used as conduits to bypass occluded arteries. Unfortunately, patency rates are limited by vein graft disease (VGD). Toll like receptors (TLRs) can be activated in vein grafts by endogenous ligands. This study aims to investigate the role of TLR3 in VGD. MethodsVein graft surgery was performed by donor caval vein interpositioning in the carotid artery of recipient Tlr2−/−, Tlr3−/−, Tlr4−/− and control mice. Vein grafts were harvested 7, 14 and 28d after surgery to perform immunohistochemical analysis. Expression of TLR-responsive genes in vein grafts was analysed using a RT2-profiler PCR Array. mRNA expression of type-I IFN inducible genes was measured with qPCR in bone marrow-derived macrophages (BMM). ResultsTLR2, TLR3 and TLR4 were observed on vein graft endothelial cells, smooth muscle cells and macrophages. Tlr3−/− vein grafts demonstrated no differences in vessel wall thickening after 7d, but after 14d a 2.0-fold increase (p = 0.02) and 28d a 1.8-fold increase (p = 0.009) compared to control vein grafts was observed, with an increased number of macrophages (p = 0.002) in the vein graft. Vessel wall thickening in Tlr4−/− decreased 0.6-fold (p = 0.04) and showed no differences in Tlr2−/− compared to control vein grafts. RT2-profiler array revealed a down-regulation of type-I IFN inducible genes in Tlr3−/− vein grafts. PolyI:C stimulated BMM of Tlr3−/− mice showed a reduction of Ifit1 (p = 0.003) and Mx1 (p < 0.0001) mRNA compared to control. ConclusionsWe here demonstrate that TLR3 can play a protective role in VGD development, possibly regulated via type-I IFNs and a reduced inflammatory response.

Systems Approach Identified PPARα as a Therapeutic Target for Vein Graft Disease: the Effects of the Specific Activator Pemafibrate on Macrophage Activation

Systems Approach Identified PPARα as a Therapeutic Target for Vein Graft Disease: the Effects of the Specific Activator Pemafibrate on Macrophage Activation

Gene therapy with antisense oligonucleotides silencing c-myc reduces neointima formation and vessel wall thickness in a mouse model of vein graft disease

Gene therapy for avoiding intimal hyperplasia of vein grafts after coronary artery bypass grafting is still discussed controversially. A promising application of gene therapy in vein grafts is the use of antisense oligonucleotides to block the expression of genes encoding cell cycle regulatory proteins in vascular smooth muscle cells. C-myc, either directly or by regulating the expression of other proteins, controls cell proliferation, apoptosis and cell survival, tissue remodeling, angiogenesis, cell metabolism, production of inflammatory and anti-inflammatory cytokines, and also participates in cell transformation.Forty C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. Twenty mice received periadventitial administration of antisense oligonucleotides directed against c-myc (treatment group), the other twenty mice received no treatment (control group). All vein grafts were harvested two weeks after surgery, dehydrated, wax embedded, cut into slides of 2 μm thickness, stained and histologically and immunohistochemically examined under light microscope.In our study, we could show the promising effects of antisense oligonucleotide treatment in a mouse model of vein graft disease including the significant reduction of neointimal, media and total vessel wall thickness with a significantly lower percentage of SMA positive cells, elastic fibres and acid mucopolysaccharides in the neointima and media, a decreased vascularization, and a lower expression of PDGFR ß, MMP-9 and VEGF-A positive cells throughout the whole vein graft wall.

Abstract 337: Short-Term Protein Restriction Attenuates Vein Graft Disease by Inhibition of Endothelial Cell Damage and Upregulates Cystathionine-g-Lyase

Objective: Short-term protein restriction (PR) preceding surgery limits ischemia reperfusion injury and arterial intimal hyperplasia in mouse models, possibly via upregulation of endogenous enzymatic production of the gaseous messenger hydrogen sulfide (H 2 S) by cystathionine-gamma-lyase (CGL). Here, we tested the hypothesis that short-term PR will limit vein graft disease (VGD) via CGL upregulation and increased H 2 S production, resulting in EC cytoprotection and reduced leukocyte transmigration. Approach and Results: LDLR -\- mice (male, 8-10 weeks old) were fed a high fat/high cholesterol (HF/HC) diet for two weeks. One group was then switched to a PR HF/HC diet with or without daily CGL inhibitor propargylglycine (PAG) injections. 7 days later mice underwent carotid interposition grafting with donor caval veins from mice on matched diets. Mice were euthanized at baseline (preop), post-op day 4 or 28 for analysis of the graft (histology, immunohistochemistry), aorta (western blot) and kidney EC (flow-cytometry). PR mice showed decreased graft intimal/media+adventitia (I/M+A) area and thickness ratios (Fig. A) on post-op day 28. Staining for CD31 and neutrophil-elastase revealed a relatively intact EC layer (Fig. B-C, CD31 in brown, red arrows, p&lt;0.001) and less neutrophil transmigration (p=0.02) on post-op day 4. PR increased baseline CGL expression in aortas (Fig. D-E) and upregulated EC H 2 S (Fig. F). Our preliminary data indicates that PAG injections during PR tended to diminish its protective effects on VGD (Fig. G). Conclusions: PR attenuated VGD via limiting of EC damage concomitant with increased CGL expression and endogenous H 2 S production. Ongoing studies will further define the CGL dependence of this process. Short-term preoperative PR stands as a potentially simple, safe, cost-efficient intervention to enhance vein graft durability.