S-EPMC7072413 - Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice. - OmicsDI

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Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice.

ABSTRACT: Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.

SUBMITTER: Parma L

PROVIDER: S-EPMC7072413 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice.

Parma Laura L Peters Hendrika A B HAB Baganha Fabiana F Sluimer Judith C JC de Vries Margreet R MR Quax Paul H A PHA

Cells 20200201 2

Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O<sub>2</sub>, 5% CO<sub>2</sub>) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogene ...[more]

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Project description:ImportanceIn vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.ObjectiveTo evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.Design, setting, and participantsData from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.InterventionsPreservation of vein grafts in saline, blood, or buffered saline solutions.Main outcomes and measuresOne-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.ResultsMost patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.Conclusions and relevancePatients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.Trial registrationclinicaltrials.gov Identifier: NCT00042081.

Project description:BackgroundArteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.MethodsWe conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.ResultsAt 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.ConclusionsTreatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Project description:OBJECTIVE:Approximately 30% of autogenous vein grafts develop luminal narrowing and fail because of intimal hyperplasia or negative remodeling. We previously found that vein graft cells from patients who later develop stenosis proliferate more in vitro in response to growth factors than cells from patients who maintain patent grafts. To discover novel determinants of vein graft outcome, we have analyzed gene expression profiles of these cells using a systems biology approach to cluster the genes into modules by their coexpression patterns and to correlate the results with growth data from our prior study and with new studies of migration and matrix remodeling. METHODS:RNA from 4-hour serum- or platelet-derived growth factor (PDGF)-BB-stimulated human saphenous vein cells obtained from the outer vein wall (20 cell lines) was used for microarray analysis of gene expression, followed by weighted gene coexpression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function was determined using short-interfering RNA to inhibit gene expression before subjecting cells to growth or collagen gel contraction assays. These cells were derived from samples of the vein grafts obtained at surgery, and the long-term fate of these bypass grafts was known. RESULTS:Neither migration nor cell-mediated collagen gel contraction showed a correlation with graft outcome. Although 1188 and 1340 genes were differentially expressed in response to treatment with serum and PDGF, respectively, no single gene was differentially expressed in cells isolated from patients whose grafts stenosed compared with those that remained patent. Network analysis revealed four unique groups of genes, which we term modules, associated with PDGF responses, and 20 unique modules associated with serum responses. The "yellow" and "skyblue" modules, from PDGF and serum analyses, respectively, correlated with later graft stenosis (P = .005 and P = .02, respectively). In response to PDGF, yellow was also associated with increased cell growth. For serum, skyblue was also associated with inhibition of collagen gel contraction. The hub genes for yellow and skyblue (ie, the gene most connected to other genes in the module), scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN), respectively, were tested for effects on proliferation and collagen contraction. Knockdown of SCARA5 increased proliferation by 29.9% ± 7.8% (P < .01), whereas knockdown of SBSN had no effect. Knockdown of SBSN increased collagen gel contraction by 24.2% ± 8.6% (P < .05), whereas knockdown of SCARA5 had no effect. CONCLUSIONS:Using weighted gene coexpression network analysis of cultured vein graft cell gene expression, we have discovered two small gene modules, which comprise 42 genes, that are associated with vein graft failure. Further experiments are needed to delineate the venous cells that express these genes in vivo and the roles these genes play in vein graft healing, starting with the module hub genes SCARA5 and SBSN, which have been shown to have modest effects on cell proliferation or collagen gel contraction.

Project description:ObjectiveTherapeutic anticoagulation (AC) is used clinically for prolongation of infrainguinal bypass patency, but evidence for the efficacy of this practice is conflicting. The objective of our study was to determine the association of AC with bypass graft primary patency.MethodsClinical and comorbid data of patients undergoing infrainguinal bypass grafts to a below-knee target with at least 1 year of follow-up performed from 2003 to 2015 were obtained from the Society for Vascular Surgery Vascular Quality Initiative. Inverse propensity of treatment-weighted Cox regression was used to assess the effect of AC on patency in the total cohort while adjusting for clinical, operative, and comorbid differences between treatment groups. Subgroup analyses of distal targets and conduit type were performed. Perioperative complications were analyzed using propensity-weighted logistic regression.ResultsWe identified 7612 bypass grafts with intact 1-year follow-up information from 2003 to 2015. The mean age was 67.5 ± 11.2 years; 30.5% (n = 2320) were female, and 28.6% (n = 2165) were discharged on therapeutic AC. The anticoagulated group had a higher rate of tibial, ankle, and pedal targets (52.1% [n = 1127] vs 47.6% [n = 2269]; P < .001), had a greater use of non-single-segment vein conduits (44.3% [n = 951] vs 26.5% [n = 1426]; P < .001), and was more likely to have had a previous ipsilateral bypass (27.2% [n = 589] vs 14.7% [n = 794]; P < .001) or stent (25.4% [n = 550] vs 20.9% [n = 1130]; P < .001). Estimated unadjusted primary patency was 70.8% ± 0.6% at 1 year and lower for anticoagulated bypasses (66.9% ± 1.2% vs 72.4% ± 0.7%; P < .001). Propensity-weighted analysis showed no significant association of AC with primary patency in the overall cohort (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.86-1.11; P = .8) but demonstrated a trend toward improvement of primary patency in those with a non-single-segment vein conduit to a below-knee popliteal target (HR, 0.85; 95% CI, 0.80-1.02; P = .09). AC was associated with significantly improved secondary patency in those with prosthetic bypass grafts (HR, 0.77; 95% CI, 0.62-0.96; P = .02) or prosthetic bypasses to an infrapopliteal target (HR, 0.72; 95% CI, 0.54-0.97; P = .02). Odds of postoperative wound complications were significantly higher in those receiving AC (odds ratio, 1.33; 95% CI, 1.11-1.61; P = .002).ConclusionsThis study does not demonstrate a significant impact of therapeutic AC on primary patency for infrainguinal bypass grafts. Treatment with AC may benefit secondary patency in those with a prosthetic bypass, especially to an infrapopliteal target, but at an increased risk of postoperative wound complications.