Objectives: Modulation of abdominal aortic aneurysm (AAA) expansion by HMG-CoA reductase inhibitors (statins) might be linked to reducing IL-6 and MMP-9, which may be consequent on reducing plasma cholesterol. Ezetimibe is a novel cholesterol absorption inhibitor used in combination with statins. This pilot study compared the biological effects of ezetimibe combination therapy with simvastatin alone on parameters relevant to aneurysm expansion including cytokines and proteolytic enzymes.Design: Randomised placebo-controlled double-blind trial.Materials & Methods: Eighteen patients scheduled for elective open AAA repair were randomised to simvastatin 40 mg plus ezetimibe 10 mg (n = 9), or simvastatin 40 mg plus placebo (n = 9), for 32.5 days (IQR 28-50.5) until the day of surgery. Total concentrations of TNF-alpha, IL-1 beta, IL-6, IL-8, IL-10, MMPs-1, -2, -3, -8, -9, -12, -13, TIMP-1 and -2 were measured in plasma, aortic wall homogenates and tissue culture explants. Results: Two patients in the placebo arm did not undergo open repair precluding aortic samples. Ezetimibe was associated with a significant reduction in aortic wall MMP-9 (p = 0.02) and aortic wall IL-6 (p = 0.02), associated with a reduction in plasma lipids.Conclusions: These results suggest that ezetimibe combination therapy reduces aortic wall proteolysis and inflammation, key processes that drive AAA expansion. A larger RCT is justified focussing on aneurysm growth rates in small AAA. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Rationale: Plasma concentration of high-density lipoprotein (HDL) is inversely proportional to the incidence of coronary artery disease, although the precise mechanism of protection remains unclear. Using activated human umbilical vein endothelial cells (HUVEC) as a model of ‘athero-prone’ endothelium, we investigated the acute transcriptional changes in response to treatment with reconstituted discoidal HDL (rHDL), to identify genes/processes important in mediating protection.

Objectives: Thrombomodulatory factors have been implicated in plaque instability. The aim was to examine the relationship between thrombomodulatory gene expression, timing of clinical events and plaque histology.Design of Study: Plaques were obtained from 40 consecutive patients undergoing carotid endarterectomy and divided into three groups (group 1, early symptomatic, within 1 month; group 2, late symptomatic, 1-6 months and group 3, asymptomatic). Total RNA was isolated to determine the expression of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), plasminogen activator inhibtor-1 (PAI-1), tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), CD68 and vascular endothelial-cadherin (VE-Cadherin).Results: Expression of t-PA, PAI-1, TF, TFPI, TM, CD68 and VE-cadherin were significantly increased in the early symptomatic group (p = 0.019, 0.028, 0.018, 0.025, 0.038, 0.016 and 0.027 respectively), but the level of gene expression in the late symptomatic group was indistinguishable from the asymptomatic group. The incidence of plaque rupture and intraplaque haemorrhage was significantly increased in the early symptomatic groups (58% versus 18%/18% group 2/3, and 55% versus 6%/9% respectively, p < 0.05 for both).Conclusions: Expression of thrombomodulatory genes is increased in unstable plaques, though levels after 1 month are comparable to asymptomatic plaques. This transient rise may influence plaque instability, and rapid resolution mirrors the clinical reduction in risk of further thromboembolic events. Crown Copyright (C) 2009 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. All rights reserved.

Interleukin-6 (IL-6) is associated with abdominal aortic aneurysm (AAA) development and is an independent risk factor for cardiovascular mortality. We tested the hypothesis that aneurysm repair reduces circulating IL-6 by comparing concentrations in patients with large AAA awaiting repair (n=50) with patients having undergone open (n=34) or endovascular (n=66) repair. Only open repair was associated with a significant reduction in IL-6 (p=0.025). These results suggest that AAAs remain biologically active following endovascular repair. Aneurysm-derived IL-6 may have serious implications for cardiovascular health, and attention should be directed to modifying cardiovascular risk factors in these patients, even after successful aneurysm repair.

OBJECTIVES:This study used the whole transcriptome approach to investigate the role of genes involved in immune and inflammatory response at the site of aneurysm rupture.MATERIALS AND METHODS:Rupture site and paired anterior sac biopsies (internal control) of ruptured abdominal aortic aneurysms (AAAs) (n=10) were analysed with Affymetrix Human Genome U133A plus 2.0 microarray. Twenty-one differentially expressed genes were selected for validation using quantitative reverse transcriptase polymerase chain reaction (QRT-PCR).RESULTS:A total of 139 genes (123 upregulated, 16 downregulated) at the aneurysm rupture site were differentially expressed (>2.5-fold, P<0.005). Immune and inflammatory responses (Gene Ontology Classification) were frequently associated with the differentially expressed genes. Genes with immune and inflammatory functions that were confirmed, by QRT-PCR, to be overexpressed at the aneurysm rupture site were interleukins-6 and -8 (IL-6 and -8), Selectin E (SELE), prostaglandin-endoperoxidase synthase 2 (COX2) and prokineticin 2 (PROK2). IL-6 (pro-immune) and IL-8 (pro-immune and pro-inflammatory) have previously been linked to aneurysm rupture; and SELE and COX2 (pro-inflammatory) have previous associations with aneurysm development but not rupture.CONCLUSIONS:The differential expression of genes involved in immune and inflammatory responses was confirmed at AAA rupture site. These genes may represent novel targets for treatment of aneurysms.

Introduction: Changes to cardiac matrix are central to ventricular remodelling after acute MI and matrix metalloproteinase expression is implicated in this process. We investigated the temporal profile of MMP-3 and its relationship to LV dysfunction and prognosis following AMI.Methods: We studied 382 patients with AMI. Plasma MMP-3 was measured at 0-12, 12-24 h and for subsequent 24 h periods during admission. LV function (LVEF) was assessed by echocardiography pre-discharge and at a median of 148 days and clinical endpoints at a median of 313 days.Results: MMP-3 peaked prior to discharge thus pre-discharge levels were used in analyses. MMP-3 was associated with patient age (p<0.001), creatinine (p<0.001) and was higher in males (p<0.001) and hypertensives (p<0.001). MMP-3 inversely correlated with LVEF at follow-up (p=0.043), was higher in subjects with LVEF <40% (p=0.017) and in subjects with increasing EDV (P=0.017) or ESV (p=0.007) compared to those in whom volumes fell between visits. In the 58 patients reaching the endpoint of death or heart failure, MMP-3 was higher (p<0.001). On Kaplan-Meier analysis, subjects with levels above optimum cut off identified via ROC curves were more likely to suffer a clinical event (p=0.037).Conclusion: MMP-3 is associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after AMI. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Extracellular matrix degradation and increased proteolytic enzyme (matrix metalloproteinase (MMP)) activity characterise abdominal aortic aneurysm formation. Post-stenotic dilatation of ascending aorta is associated with aortic stenosis and regurgitation, haemodynamically normal bicuspid aortic valve (BAV) and following AV replacement. We aimed to determine an association between ascending aortic pathology and abnormal AV, with particular reference to MMPs, and ascertain differences between BAV and tricuspid (TAV) AV. Subset of the study population (n=19) with a preoperative ascending aorta of >4 cm was analysed. Samples of ascending aorta and AV were obtained from 82 patients (TAV, n=54, BAV, n=28) undergoing surgery. Gene expression of MMP-1, -2, -9 and tissue inhibitor of metalloproteinase (TIMP)-1 and -2 was quantified by real-time RT-PCR. No significant difference was seen in gene expression level of MMPs, TIMPs and ratio of MMPs/TIMPs in ascending aorta and AV between patients with BAV and TAV. MMP-2/TIMP-1 in ascending aorta was greater in BAV, in the subset of patients with preoperative aortic dilatation (P<0.05). No difference exists in gene expression of MMPs in ascending aorta and AV between patients with BAV and TAV. However, patients with larger aortic diameters have increased MMP-2/TIMP-1. Modifying MMP expression may have a role in development of aneurysms.

Objective: Abdominal aortic aneurysm (AAA) development is associated with increased angiogenesis and overexpression of vascular endothelial growth factor (VEGF). Inhibition of angiogenesis results in attenuation of experimental aneurysms. This study investigated the effects of recombinant human (rh)VEGF on experimental aneurysms.Methods: Apolipoprotein E-deficient (apoE(-/-)) mice were assigned to one of four groups: (1) normal saline infusion (sham), (2) angiotensin-II (AngII) infusion, (3) AngII infusion plus 100 mu g daily rhVEGF for 14 days (AngII + 14dVEGF), or (4) AngII infusion plus 100 mu g daily rhVEGF for 21 days (AngII + 21dVEGF). Aortic maximum diameter and cross-sectional area were determined by magnetic resonance imaging and microscopy. All mice were sacrificed at day 28.Results: Aneurysms developed in all mice in the AngII+14dVEGF and AngII+21dVEGF groups by day 21 compared with 40% in the AngII group. Treatment with rhVEGF increased maximum aortic diameter (P <.002) and crosssectional area of aneurysms (P <.005) at day 21. This effect was maintained at day 28 (P <.0005). Decreasing rhVEGF treatment from 21 to 14 days did not attenuate aneurysm formation. Treatment with rhVEGF upregulated matrix metalloproteinase 2 gene expression within the aortic wall (P <.0009).Conclusions: Treatment with rhVEGF intensified the formation of Angll-induced aneurysms. Further studies are needed to investigate if antiangiogenic therapy may be a valid medical therapy against aneurysm expansion or rupture. (J Vase Surg 2010;52:159-66.)

Background: Multiple infusions of HDLs have been shown to mediate approximately 4% reduction in plaque volume. This may relate to removal of intra-plaque lipid, but the precise mechanism is unknown. To test the hypothesis that HDLs may influence plaque stabilisation through modulating transcription, we examined the effects of a single dose of rHDL on expression of thrombomodulatory genes in carotid plaques. Materials and Methods: Forty patients undergoing carotid endarterectomy (CEA) were stratified to three groups: early symptomatics ( n =12, stroke/transient ischemic attack (TIA) 1month before CEA)late symptomatics ( n =14, stroke/TIA > 1month before CEA); and asymptomatics ( n =12). RNA was isolated from plaques following CEA, and expression of the thrombomodulatory genes, tissue factor (TF); tissue factor pathway inhibitor (TFPI); thrombomodulin (TM); tissue type plasminogen activator (tPA); urokinase plasminogen activator (uPA); plasminogen activator inhibitor-1 (PAI-1), measured using QRT-RT-PCR. Nine patients with early symptomatic carotid disease, undergoing CEA, were then randomised to infusion of reconstituted HDL (rHDL) 80mg/kg Apo A-I ( n =4) or a similar volume of phosphate buffered saline ( n =5). Plaque specimens were collected 24 hrs later and RNA isolated for QRT-RT- PCR measurement of thrombomodulatory gene expression. Results: A significant difference in TF, TM, tPA and PAI-1 genes were observed in the 3 patient groups (see Table 1 ). In the rHDL group, a single dose of rHDL reduced the expression of TF (0.71 (0.65–0.75) vs 0.98 (0.81–1.14), P=0.05). No significant difference was observed in other thrombomodulatory factors between the 2 groups. Conclusions: Plaque stabilisation, which occurs within one month of a clinical event may be facilitated, at the transcriptional level, following rHDL infusion. We hope to report a larger double blind placebo controlled trial which will determine the full effects of rHDLs on plaque stability. Table 1