Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

AbstractPurpose: Pathologic remodeling of the extracellular matrix is a critical mechanism in the development and progression of abdominal aortic aneurysms (AAAs). Although angiotensin-converting enzyme (ACE) inhibitors are known to alter vascular wall remodeling in other conditions, their effects on AAAs are unknown. In this study we assessed the effect of ACE inhibitors in a rodent model of aneurysm development. Methods: Male Wistar rats underwent transient aortic perfusion with porcine pancreatic elastase, followed by treatment with one of three ACE inhibitors (captopril [CP], lisinopril [LP], or enalapril [EP]), an angiotensin (AT)1 receptor antagonist (losartan [LOS]), or water alone (9 rats in each group). Blood pressure and aortic diameter (AD) were measured before elastase perfusion and on day 14, with an AAA defined as an increase in AD (ΔAD) of more than 100%. The structural features of the aortic wall were examined by means of light microscopy. Results: Aneurysmal dilatation consistently developed within 14 days of elastase perfusion in untreated rats, coinciding with the development of a transmural inflammatory response and destruction of the elastic media (mean ΔAD, 223% ± 28%). All three ACE inhibitors prevented AAA development (mean ΔAD: CP, 67% ± 4%; LP, 18% ± 12%; and EP, 14% ± 3%; each P <.05 vs controls). ACE inhibitors also attenuated the degradation of medial elastin without diminishing the inflammatory response. Surprisingly, the aneurysm-suppressing effects of ACE inhibitors were dissociated from their effects on systemic hemodynamics, and LOS had no significant effect on aneurysm development compared with untreated controls (mean ΔAD, 186% ± 19%). Conclusion: Treatment with ACE inhibitors suppresses the development of elastase-induced AAAs in the rat. Although this is associated with the preservation of medial elastin, the mechanisms underlying these effects appear to be distinct from hemodynamic alterations alone or events mediated solely by AT1 receptors. Further studies are needed to elucidate how ACE inhibitors influence aortic wall matrix remodeling during aneurysmal degeneration. (J Vasc Surg 2001;33:1057-64.

Two loop effective potential for < A^2_\mu > in the Landau gauge in quantum chromodynamics

We construct the effective potential for the dimension two composite operator 1/2 A^{a 2}_\mu in QCD with massless quarks in the Landau gauge for an arbitrary colour group at two loops. For SU(3) we show that an estimate for the effective gluon mass decreases as N_f increases.Comment: 17 latex page

Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

AbstractPurpose: Pathologic remodeling of the extracellular matrix is a critical mechanism in the development and progression of abdominal aortic aneurysms (AAAs). Although angiotensin-converting enzyme (ACE) inhibitors are known to alter vascular wall remodeling in other conditions, their effects on AAAs are unknown. In this study we assessed the effect of ACE inhibitors in a rodent model of aneurysm development. Methods: Male Wistar rats underwent transient aortic perfusion with porcine pancreatic elastase, followed by treatment with one of three ACE inhibitors (captopril [CP], lisinopril [LP], or enalapril [EP]), an angiotensin (AT)1 receptor antagonist (losartan [LOS]), or water alone (9 rats in each group). Blood pressure and aortic diameter (AD) were measured before elastase perfusion and on day 14, with an AAA defined as an increase in AD (ΔAD) of more than 100%. The structural features of the aortic wall were examined by means of light microscopy. Results: Aneurysmal dilatation consistently developed within 14 days of elastase perfusion in untreated rats, coinciding with the development of a transmural inflammatory response and destruction of the elastic media (mean ΔAD, 223% ± 28%). All three ACE inhibitors prevented AAA development (mean ΔAD: CP, 67% ± 4%; LP, 18% ± 12%; and EP, 14% ± 3%; each P <.05 vs controls). ACE inhibitors also attenuated the degradation of medial elastin without diminishing the inflammatory response. Surprisingly, the aneurysm-suppressing effects of ACE inhibitors were dissociated from their effects on systemic hemodynamics, and LOS had no significant effect on aneurysm development compared with untreated controls (mean ΔAD, 186% ± 19%). Conclusion: Treatment with ACE inhibitors suppresses the development of elastase-induced AAAs in the rat. Although this is associated with the preservation of medial elastin, the mechanisms underlying these effects appear to be distinct from hemodynamic alterations alone or events mediated solely by AT1 receptors. Further studies are needed to elucidate how ACE inhibitors influence aortic wall matrix remodeling during aneurysmal degeneration. (J Vasc Surg 2001;33:1057-64.

Outcomes of percutaneous endovascular intervention for type II endoleak with aneurysm expansion

ObjectiveType II endoleak (T2EL) with aneurysm expansion is believed to place patients at risk for aneurysm-related mortality (ARM). Treatment with glue and/or coil embolization of the aneurysm sac, inferior mesenteric artery (IMA), and lumbar branches via translumbar or transarterial approaches has been utilized to ablate such endoleaks, and thus decrease ARM. We evaluated the midterm results of percutaneous endovascular treatment of T2EL with aneurysm expansion.MethodsSingle-institution, 5-year (January 2003 to August 2008) retrospective study of all endovascular interventions for T2EL with sac expansion. Blinded, independent review of all available pre- and post-T2EL intervention computed tomography (CT) scans was performed. Aneurysm sac maximal transverse diameters and aneurysm sac growth rates prior to and following T2EL intervention were analyzed.ResultsForty-two patients (34 male, eight female; mean age, 75) underwent T2EL intervention at 26 ± 20 months after endovascular aneurysm repair (EVAR) and were subsequently followed for 23 ± 20 months. Seven out of 42 patients (17%) underwent repeat T2EL intervention. Interventions included 44 translumbar sac embolizations, and transcatheter embolizations of nine IMAs and seven lumbar/hypogastric arteries. Aneurysm diameter was 6.1 ± 1.6 cm at EVAR, 6.6 ± 1.5 cm at initial T2EL treatment, and 6.9 ± 1.7 cm at last follow-up. There were no significant differences in the rates of aneurysm sac growth pre- and post-T2EL treatment. At last follow-up imaging, recurrent or persistent T2EL was noted in 72% of patients. Of 42 patients, nine (21%) received operative endoluminal correction of occult type I or type III endoleaks that were diagnosed during the T2EL angiographic intervention. There were no aneurysm ruptures or ARMs during follow-up; overall mortality for the 5-year study period was 24%.ConclusionsIn this series, percutaneous endovascular intervention for type II endoleak with aneurysm sac growth does not appear to alter the rate of aneurysm sac growth, and the majority of patients display persistent/recurrent endoleak. However, diagnostic angiographic evaluation may reveal unexpected type I and III endoleaks and is therefore recommended for all patients with T2EL and sac growth. While coil and glue embolization of aneurysm sac and selected branch vessels does not appear to yield benefit in our series, the diagnosis and subsequent definitive treatment of previously occult type I and III endoleaks may explain the absence of delayed rupture and ARM in our series

Overt ischemic colitis after endovascular repair of aortoiliac aneurysms

AbstractObjectiveControversy exists as to the cause of ischemic colitis complicating endovascular aneurysm repair. Occlusion of the hypogastric arteries (HAs) during endovascular repair of aortoiliac aneurysms (AIAs) results in a significant incidence of buttock claudication, and has been suggested as a causative factor in the development of postprocedural colonic ischemia, in addition to factors such as systemic hypotension, embolization of atheromatous debris, and interruption of inferior mesenteric artery inflow. To analyze the relationship between perioperative HA occlusion and postoperative ischemic colitis, we reviewed our experience over 2 years with Food and Drug Administration–approved endovascular graft devices for treatment of AIAs.MethodsElective repair of AIAs with bifurcated endovascular grafts was performed in 233 patients over a 2-year period. These included 184 AneuRx grafts, 17 Ancure grafts, and 32 Excluder grafts. During the experience, 44 patients (18.9%) underwent unilateral perioperative HA occlusion (28 right, 16 left) during the course of endovascular AIA repair, and 1 patient (0.4%) underwent bilateral HA occlusion.ResultsIn 4 patients (1.7%) signs and symptoms of ischemic colitis developed 2.0 ± 1.4 days postoperatively. In all patients the diagnosis was confirmed at sigmoidoscopy, and initial treatment included bowel rest, hydration, and intravenous antibiotic agents. Three patients with bilateral patent HAs required colonic resection 14.7 ± 9.7 days after the initial diagnosis, and 2 of these 3 patients died in the postoperative period. Pathologic findings confirmed the presence of atheroemboli in the colonic vasculature in all 3 patients who underwent colonic resection. The fourth patient had undergone multiple manipulations of the left HA in an unsuccessful attempt to preserve patency of this vessel during AIA repair. This patient recovered completely with nonoperative management. Perioperative unilateral HA occlusion was not associated with a significantly higher incidence of postoperative ischemic colitis.ConclusionPerioperative HA occlusion during aortoiliac open or endovascular surgery may contribute to development of the rare but potentially lethal complication of ischemic colitis. However, our extensive experience suggests that embolization of atheromatous debris to the HA tissue beds during endovascular manipulations, rather than proximal HA occlusion, is the primary cause of clinically significant ischemic colitis after endovascular aneurysm repair

Remarks on a class of renormalizable interpolating gauges

A class of covariant gauges allowing one to interpolate between the Landau, the maximal Abelian, the linear covariant and the Curci-Ferrari gauges is discussed. Multiplicative renormalizability is proven to all orders by means of algebraic renormalization. All one-loop anomalous dimensions of the fields and gauge parameters are explicitly evaluated in the MSbar scheme.Comment: 24 pages. no figure

Three loop MSbar renormalization of QCD in the maximal abelian gauge

We determine the three loop anomalous dimensions of the quark, centre and off-diagonal gluons, centre and off-diagonal ghosts and the gauge fixing parameters in the maximal abelian gauge for an arbitrary colour group in the MSbar renormalization scheme at three loops. We show that the three loop MSbar beta-function emerges from the renormalization of the centre gluon and also deduce the anomalous dimension of the BRST invariant dimension two mass operator. Moreover, we demonstrate that in the limit that the dimension of the centre of the group tends to zero, the anomalous dimensions of the quarks, off-diagonal gluons and off-diagonal ghosts tend to those of the quarks, gluons and ghosts of the Curci-Ferrari gauge respectively.Comment: 25 latex page

Super Yang-Mills on the lattice with domain wall fermions

The dynamical N=1, SU(2) Super Yang-Mills theory is studied on the lattice using a new lattice fermion regulator, domain wall fermions. This formulation even at non-zero lattice spacing does not require fine-tuning, has improved chiral properties and can produce topological zero-mode phenomena. Numerical simulations of the full theory on lattices with the topology of a torus indicate the formation of a gluino condensate which is sustained at the chiral limit. The condensate is non-zero even for small volume and small supersymmetry breaking mass where zero mode effects due to gauge fields with fractional topological charge appear to play a role.Comment: LaTeX, 35 pages, 11 eps figures. A few changes in sec. 5.3, figure 11 added. To appear in Phys. Rev.

Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19

ABSTRACT: BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM) database. METHODS: Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22) were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. RESULTS: Several SNPs were nominally associated with AAA (p < 0.05). The SNPs with most significant p-values were located near the CCAAT enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP) database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. CONCLUSIONS: Association testing of the functional positional candidate genes on the AAA1 locus on chromosome 19q13 demonstrated nominal association in three genes. PEPD and CD22 were considered the most promising candidate genes for altering AAA risk, based on gene function, association evidence, gene expression, and protein expression

Gene Expression Signature in Peripheral Blood Detects Thoracic Aortic Aneurysm

BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA