Abstract Abdominal Aortic Aneurysm Research Articles

Abstract 304: Chemokine Receptor CCR2 Mediates Monocyte Mobilization and Migration in Experimental Aneurysms

Abdominal aortic aneurysm (AAA) is a macrophage-driven vascular inflammatory disease. Chemokine receptor CCR2, a critical mediator of monocyte mobilization and migration, promotes AAA pathogenesis in hyperlipidemic mice following angiotensin II infusion. This study examined the role o CCR2 signaling in AAA formation in a mechanistically distinct experimental aneurysm model. AAAs were created in 10 week old male CCR2 knockout (KO) and wild type C57BL/6J mice via transient intra-aortic porcine pancreatic elastase (PPE) infusion. Aneurysm progression and aortic cellularity were evaluated using ultrasonography, histology and FACS analyses. In CCR2 KO mice, minimal aneurysmal enlargement was apparent following PPE infusion. Histologically, aortic medial elastin and smooth muscle cellularity were minimally degraded, and mural macrophage accumulation and angiogenesis were also significantly reduced compared to WT mice. Significantly fewer circulating and splenic inflammatory monocytes were identified via FACS analysis in KO mice, with a reciprocal increase in bone marrow monocyte cellularity. In in vivo monocyte migration assays, CCR2 deficiency was associated with a 60 -70% reduction in migration of intravenously transferred monocytes into aneurysmal aortae. In conclusion, targeted deletion of CCR2 in mice profoundly reduces mobilization of inflammatory monocytes from the bone marrow, while suppressing aneurysmal degeneration following PPE infusion. CCR2 signaling may represent an attractive target for therapeutic inhibition in medical management of AAA disease.

OPEN VERSUS ENDOVASCULAR REPAIR OF ABDOMINAL AORTIC ANEURYSM IN THE ELECTIVE AND EMERGENT SETTING IN A POOLED POPULATION OF 37,781 PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abdominal aortic aneurysm (AAA) affects approximately 5% of males over the age of 65. Open aneurysm repair (OAR) has been performed since the 1950s, however, the performance of endovascular repair (EVAR) of both elective and ruptured AAA has steadily increased. We aimed to evaluate the incidence of

Adrenomedullin Does Not Contribute toward the Development of Abdominal Aortic Aneurysm in Mice

Abdominal aortic aneurysm (AAA) develops based on advanced atherosclerosis; however, the underlying pathogenesis remains unknown. Adrenomedullin (AM) is widely expressed in various human and rodent tissues, and has been reported to protect blood vessels. We have previously reported that AM is produced in mast cells of human AAA and that AM exhibited the antifibrotic activity of mast cell-derived AM on fibroblasts. In the present study, we investigated the role of AM in the development of AAA in 12-week-old male apolipoprotein (apo)E﹣/﹣ mice bred with AM heterozygous, or its role when recombinant human (rh) AM was administrated to the apoE﹣/﹣ male mice, which was infused with 1000 ng/kg/min of angiotensin II (Ang II) for 28 days. The incidence of the development of AAA in Ang II-infused apoE﹣/﹣ AM﹢/﹣ mice did not change compared with that in apoE﹣/﹣ mice (33.3% vs. 47.4%, p = 0.2333). In addition, rhAM administration had little effect on the incidence of the development of AAA formation (AM: 0 ng/kg/hr 47.4%; 300 ng/kg/hr 36.4%; 3000 ng/kg/hr 27.3%; p = 0.2595). In conclusion, this study suggests that AM does not contribute toward the development of AAA.

Abstract 47: Caveolin-1 is Critical for Abdominal Aortic Aneurysm Induced by Angiotensin II

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests a role of angiotensin II (Ang II) in abdominal aortic aneurysm (AAA) formation. However, the Ang II-sensitive proximal signaling events primarily responsible for AAA formation remain unclear. We recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role for development of AAA by Ang II via regulation of ADAM17. 8 week old male Cav1-/- and the control C57Bl/6 wild-type mice (WT) were co-infused with Ang II (1 μg/kg/min) and β-aminopropionitrile (BAPN: 150mg/kg/day) for 4 weeks to induce AAA. In WT with the co-infusion, 58% (14/24) were dead due to aortic rupture/dissection. All surviving WT with co-infusion had AAA with max diameter (mm) of 2.6±0.18 vs 0.93±0.09 with saline infusion (p<0.01). In contrast, we found that Cav1-/- with co-infusion did not die or develop AAA. The max diameter (mm) of AAA in Cav1-/- with co-infusion was 1.0±0.04 vs 1.1±0.06 with saline infusion (n=7). In contrast, both WT and Cav1-/- with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 151±5 vs 161±7). We found an increased expression of ADAM17 by IHC and qPCR, and enhanced phosphorylation of EGFR by IHC in WT abdominal aortae with aneurysms. These events were markedly attenuated in Cav1-/- aorta with co-infusion (ADAM17/18S mRNAx10,000 = 3.08±0.71 vs 0.97±0.42 p<0.05, n=4). Furthermore, Cav1-/- aortae showed less ER and oxidative stress compared to WT aortae assessed by IHC. In addition, Cav1 silencing induced by adenovirus encoding Cav1 targeting siRNA embedded miRNA in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 and presumably vascular caveolae microdomains appear to play a critical role in the formation of AAA by Ang II via regulation of the ADAM17/EGFR signaling and subsequent ER/oxidative stress.

Endovascular repair with chimney technique of abdominal aortic aneurysm with hostile aortic neck

Abdominal aortic aneurysm (AAA) with hostile aortic neck is not a good candidate for conventional endovascular aneurysm repair (EVAR), and a recent paper showed that EVAR with chimney technique (Ch-EVAR) yielded reasonable outcome. We report here a case of successful Ch-EVAR treatment of AAA with hostile neck. An 81-year-old man presented with a 71-mm AAA during evaluation of a gastric ulcer. Aortic neck was 30 mm in diameter, 10-15 mm in length and angulated by 100°. EVAR was performed with chimney stenting to both renal arteries, and the patient recovered after transient hematuria. At one-year follow-up, AAA had increased by 7 mm with delayed type I endoleak control without renal insufficiency. The patient needed close follow-up.

Statin Use in Aortic Aneurismal Disease to Prevent Progression and Cardiovascular Events: Review of Experimental and Clinical Data

Abdominal aortic aneurysm (AAA) is a significant health problem in the elderly. Efforts to limit the mortality rate depend on early detection and elective AAA repair. The benefit of early detection of AAAs, by ultrasound screening is limited since early repair of small AAA has been shown to provide no clinical advantage. There is currently no established pharmacotherapeutic treatment for small AAAs. In the first part of this review, we describe the potential mechanisms whereby statins can modulate the pathological processes associated to experimental and human AAA. Among them, statins are able to regulate leukocyte recruitment and immuno-inflammatory responses, platelet activation, oxidative stress, proteolysis and extracellular matrix breakdown. However, controversial results have been obtained in experimental models of AAA. In the second part of this review, we analyze the effect of statins in both, cardiovascular events on AAA patients and AAA growth. Although statin treatment is recommended for all AAA patients with the aim of reducing the incidence of cardiovascular events and death, controversial results have been shown between experimental and clinical studies regarding the potential preventive effect on AAA growth. One potential reason for these discrepancies could be related to the fact that statins reduce total cholesterol concentrations but do not modify HDL concentrations, the most sensitive predictor of AAA among lipid markers. In this respect, it could be of interest to test the effect of drugs modulating plasma HDL concentrations on AAA evolution.

Abstract 279: Role of Caveolin-1 in Abdominal Aortic Aneurysm induced by Angiotensin II

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests that activation of the AT1 receptor by angiotensin II (AngII) in AAA formation. While several downstream signals and target proteins have been identified in this pathway, there is a huge void in our knowledge regarding the AngII-sensitive proximal events primarily responsible for AAA formation. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation which linked to vascular remodeling induced by AngII. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of caveolae, in the vasculature plays a critical role for development of AAA via its regulation on ADAM17. 8 week old male Cav1-/- mice and the control C57Bl/6 wild-type (WT) mice were co-infused with AngII and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that Cav1-/- mice did not develop AAA compared to C57Bl/6 mice in spite of hypertension assessed by telemetry in both groups. This finding suggests that the AngII signaling essential for vascular contraction remains in place in Cav1-/- mice. We found an increased expression of ADAM17 and auto-phosphorylation of EGFR in WT abdominal aortae with aneurysms that were markedly attenuated in Cav1-/- mice infused with AngII+BAPN. Furthermore, Cav1-/- mice with the infusion showed less oxidative stress and ER stress than their WT counterparts as assessed by nitrotyrosine staining and KDEL/p-eIF2a staining, respectively. In conclusion, Cav1 and presumably vascular caveolae micro-domain appear to play a critical role in the formation of AAA in mice via regulation of the ADAM17/EGFR signaling axis and subsequent induction of ER/oxidative stress.

GT Microsatellite Repeats in the Heme Oxygenase-1 Gene Promoter Associated with Abdominal Aortic Aneurysm in Croatian Patients

Abdominal aortic aneurysm (AAA) is a complex genetic disorder caused by the interplay of genetic and environmental risk factors. The number of (GT)(n) repeats in the heme oxygenase-1 (HO-1) gene promoter modulates transcription of this enzyme, which might have anti-inflammatory, antioxidant, antiapoptotic, and antiproliferative effect. The distribution of alleles and genotypes in Croatian individuals genotyped for the (GT)(n) HO-1 polymorphism was similar to that in other European populations. Frequency of the short (S) alleles (GT < 25) was higher in AAA patients (41.9%) than in non-AAA individuals (28.2%, p = 0.0026) because there were more SL heterozygotes among the AAA patients. The SL genotype appeared to increase the risk for AAA, but the increase was not statistically significant after adjustment for age, sex, smoking, hypertension, and hyperlipidemia (OR = 1.53, 95% CI 0.90-3.09, p = 0.062). These findings contradict those of the only other study performed so far on the association of (GT)(n) HO-1 polymorphism and AAA.

Opening Pandora's box: The experiences of having an asymptomatic aortic aneurysm under surveillance

Abdominal aortic aneurysm (AAA) is a ballooning-out of the aorta that does not normally give any symptoms. Undetected and untreated an aortic aneurysm can rupture, which in most cases is fatal. Mass screening of 65-year old men for the early detection of AAA and, in selected cases, operation seem to reduce mortality due to rupture, although, screening has not reduced the overall mortality in this group. In Västra Götaland, the southwest part of Sweden, screening for AAA amongst 65-year old men started in 2009. There are controversies within the medical community about the benefits and adverse effects of screening. In order to explore men's experiences of being screened and knowing they had an aortic aneurysm, we undertook a qualitative interview study with 15 men who in the screening programme were identified as having an aortic aneurysm and who were to be followed-up with annual ultrasonic examinations for an indeterminate number of years. The interviews were analysed for categories and themes using content analysis. The study found that the men were ambivalent about the knowledge that they had an AAA and about the follow-up monitoring. They appreciated having the knowledge but it was accompanied by worry, feelings of anxiety and existential thoughts about the fragility and finiteness of life. We recommend that before a screening programme is implemented, the psycho-social consequences should be thoroughly investigated. Participants should be given adequate and understandable information about the consequences of screening so that they can make an informed choice whether to participate or not.

Abstract 66: TLR2 Signaling Protects Against Angiotensin II--Mediated AAA Formation in ApoE -/- Mice

Abdominal aortic aneurysm (AAA) is a potentially life-threatening degenerative vascular disease that affects 6-9% of men over 65. Although Toll-like receptors (TLRs) mediate the innate immune response resulting in the recruitment of inflammatory cells to the site of a range of pathogen-associated molecular patterns, they have also been implicated in immune tolerance. To determine the role of TLR2 signaling in AAA formation we compared AAA formation in ApoE -/- and ApoE-/-TLR2 -/- DKO mice using a mouse model for angiotensin II (ANGII) mediated AAA formation. Treatment of ApoE -/- mice with Alzet pumps releasing 750 ng/kg/min ANG II resulted in formation of AAAs in 75% of mice (n=23) and a mean increase in aortic diameter from 1.0 mm in saline treated controls to 2.15±0.15 mm, p&lt;0.001 with no effect on the thoracic aorta and the aortic arch. Although the incidence of AAAs in ApoE-/-TLR2 -/- DKO mice compared to ApoE -/- alone was unchanged, of the 12 ApoE-/-TLR2-/-DKO who developed AAAs, half demonstrated severe aneurismal involvement of the aortic arch and thoracic aorta compared to the ApoE -/- group consistent with a protective effect of TLR2. To test this hypothesis, mice were pretreated with PAM3, 50ug/ mouse/week. The incidence of AAA formation decreased to 32% in PAM 3 treated mice and aortic diameter decreased to 1.17±0.08 (n=18, p&lt;0.001) compared to ANGII alone. PAM3 had no effect on blood pressure or lipid levels. Furthermore, treatment with PAM3 after a 7 day ANG II infusion decreased the incidence of AAA to 53%. ANG II stimulated expression of the cytokines RANTES and CXCl10 and the receptor CCR5 more than 8 fold as measured by ELISA and western blot respectively; PAM3 treatment of these ANG II infused mice decreased expression to control levels in association with decreased macrophage infiltration. Finally, while ANG II increased the ratio of M1/M2 macrophages in the abdominal aorta by 2 fold, PAM3 treatment reversed the effect of ANG II on M1/M2 in aortas of mice that did not develop AAAs. Thus TLR2 stimulation protected the abdominal aorta from ANG II mediated AAA at least in part by attenuating recruitment of macrophages and expression of chemokines and chemokine receptors.

Abstract 86: Apo(a) Inhibits Plasminogen-Dependent Abdominal Aortic Aneurysm Formation in Transgenic Mice

Abdominal Aortic Aneurysm (AAA) is a lethal disorder found primarily in adults over 65. Unlike coronary heart disease, the incidence of AAA is rapidly increasing, and currently there is no nonsurgical treatment. AAA is a chronic inflammatory disease that includes early leukocyte infiltration, destruction of the elastic lamina and extracellular matrix, expansion of the aorta, and eventually fatal aorta rupture. Components of the plasminogen (Plg) and MMP pathways that mediate leukocyte infiltration are prominent in AAA. The goal of this study is to investigate regulators of these pathways in AAA, namely the inhibition Plg by apo(a). In AAA patients, the association of elevated Lp(a) and progression of AAA is controversial. Apolipoprotein(a) [apo(a)], a component of lipoprotein(a) [Lp(a)], has a high homology to Plg, and interferes with Plg functions in vitro. In our previous studies apo(a), independent of Plg, inhibited neutrophil recruitment in a peritonitis model of inflammation, and in Plg deficient mice macrophage infiltration was impaired in CaCl2 induced AAA formation. Our hypothesis is that apo(a) inhibits AAA formation by reducing neutrophil or macrophage infiltration by interfering with Plg. To test our hypothesis, the CaCl2 induced AAA model was performed in 5 strains of mice: WT; Plg-/-; apo(a)tg; apo(a)tg:Plg-/-; and Lp(a)tg mice (6-14 mice analyzed per genotype). Three weeks after injury, the WT aorta diameter increased from 0.54 to 0.88mm (62%). The diameter changed in WT 0.31±0.11mm, apo(a)tg 0.06±0.02mm, apo(a):Plg -/- 0.39±0.07mm and Lp(a) 0.08±0.07mm. The dilation was significantly lower in apo(a) and Lp(a) mice compared to WT (P&lt;0.001). The H&amp;E, Trichrome and EVG stain showed elevated leukocyte infiltration in WT and apo(a):Plg -/- injured aorta, accompanied by thining of the media layer and elastic lamellae fragmentation. In contrast, the aorta of apo(a) mice remained preserved. Neutrophils and macrophages were decreased in apo(a) mice compared to WT(P&lt;0.05). In apo(a):Plg -/- mice, only neutrophil infiltration was decreased not macrophages. These results suggest that inhibition of neutrophils in apo(a) mice is independent of Plg, but reduced macrophage infiltration in apo(a) mice is Plg-dependent during AAA formation.

Intravascular Sonography Assessment of a Type III Endoleak of an Aortic Endograft

Abdominal aortic aneurysm (AAA) is a common disease in today’s older population. When AAAs grow large, the risk for rupture becomes high, and the AAA should be treated. It can be treated in one of two ways: open or endovascular repair. With endovascular repair, an endograft is placed within the aorta using angiographic guidance to exclude the AAA. Intravascular sonography (IVUS) can be used as an adjunct to angiography for the endovascular repair. The endograft must then be routinely followed for complications such as endoleak. This case report identifies a symptomatic type III endoleak and describes how IVUS is used in conjunction with computed tomography and angiography to treat type III endoleaks.

Single-Center Experience and 1-Year Follow-up Results of “Sandwich Technique” in the Management of Common Iliac Artery Aneurysms During EVAR

Abdominal aortic aneurysm (AAA) accompanied by common iliac artery (CIA) aneurysms requires a more demanding procedure owing to the difficulties in obtaining an adequate distal landing zone for the stent-graft limb(s), a potential site of endoleak. The "sandwich technique" is a procedure to increase EVAR feasibility in the setting of adverse or challenging CIA anatomy. Its main advantages include no restrictions in terms of CIA diameter or length or internal iliac artery (IIA) diameter, no need to wait for a specific stent-graft. Our purpose is to describe our single-center experience and one year follow-up results of this new procedure. From April 2009 to June 2010, the sandwich technique was performed in our institution in 7 patients treated for AAA and unilateral CIA aneurysms (n. 5) or bilateral CIA aneurysms (n. 2). Inclusion criteria were the presence of unilateral or bilateral CIA aneurysm (independently from its diameter), IIA artery measuring up to 9 mm in its maximum diameter, not dilatation of IIA and EIA. The mean follow-up length was 15 months (range: 14-20 months). All stent-implanted iliac branches remained patent on 1 year follow-up and IIA flow was preserved. None of the patients had symptoms of pelvic ischemia. CT scan follow-up showed aneurysm shrinkage in five patients, without any sign of endoleaks in all cases. In selected cases, the "sandwich technique" showed good outcomes confirming to be a safe and easy to perform way to overcome anatomical constraints and expanding the limits of EVAR.

Recent Advances in Pharmacotherapy Development for Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a common disease causing segmental expansion and rupture of the aorta with a high mortality rate. The lack of nonsurgical treatment represents a large and unmet need in terms of pharmacotherapy. Advances in AAA research revealed that activation of inflammatory signaling pathways through proinflammatory mediators shifts the balance of extracellular matrix (ECM) metabolism toward tissue degradation. This idea is supported by experimental evidence in animal models that pharmacologic intervention at each pathological step can prevent AAA development. Previously, we identified c-Jun N-terminal kinase (JNK), a pro-inflammatory signaling molecule, as a therapeutic target for AAA. Abnormal activation of JNK in AAA tissue regulates multiple pathological processes in a coordinated manner. Pharmacologic inhibition of JNK tips the ECM balance back towards repair rather than degradation. Interventions targeting signaling molecules such as JNK in order to manipulate multiple pathological processes may be an ideal therapeutic strategy for AAA. Furthermore, the development of biomarkers as well as appropriate drug delivery systems is essential to produce clinically practical pharmacotherapy for AAA.

Genomic Research to Identify Novel Pathways in the Development of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a common disease with a large heritable component. There is a need to improve our understanding of AAA pathogenesis in order to develop novel treatment paradigms. Genomewide association studies have revolutionized research into the genetic variants that underpin the development of many complex diseases including AAA. This article reviews the progress that has been made to date in this regard, including mechanisms by which loci identified by GWAS may contribute to the development of AAA. It also highlights potential post-GWAS analytical strategies to improve our understanding of the disease further.

Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue

Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. In ex vivo cultures of human AAA tissue, exogenously added HGF in the presence of tumor necrosis factor-alpha (TNF-α) enhanced the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and suppressed the secretion of proinflammatory monocyte/macrophage chemotactic protein-1 (MCP-1). The angiotensin converting enzyme (ACE) inhibitors, imidaprilat and perindoprilat, enhanced the secretion of endogenous HGF, augmented the TNF-α-induced IL-10 secretion and suppressed MCP-1 secretion from AAA tissue. The ACE inhibitors also augmented the expression of HGF in the presence of bradykinin in human aortic endothelial cells in culture (HAECs). In contrast, HGF secretion was not affected by either an angiotensin II type 1 receptor (AT1) antagonist or angiotensin II in AAA tissue or in HAECs. These results suggested that angiotensin converting enzyme inhibitors may be useful in controlling chronic inflammation in AAA, partly due to their enhancement of HGF secretion.

What Should Be Done if There Is Coronary Artery Disorder in Ruptured Abdominal Aortic Aneurysm?

Abdominal aortic aneurysm (AAA) is the most common type of aneurismal diseases. Generally, it is asymptomatic and when it is ruptured, it develops with high morbidity and mortality. Case report: A 62-years-old male patient consulted our emergency with a pain at his dorsum and lumbar part. Cardiologist with a suspicion of coronary artery disorder or dissection, coronary angiography was executed. Consecutive lesions of LAD artery (left anterior descending) 40% - 50% and 90%, CX artery (circumflex) 40% and 80% - 90%, and a lesion of RCA (right coronary artery) 20% - 30% were detected. With a suspicion of rupture, abdominal aneurysm tomography (CT) was demanded. In the tomography, a 7-cm-diameter ruptured abdominal aortic aneurysm was diagnosed. Levosimendan support was started. Under the support of levosimendan a Y graft operation was performed. The operation was ended up with levosimendan support considering that coronary bypass would increase mortality and morbidity. Discussion: Approximately 50% of the ruptured aneurysms are died before they reach hospital while the 30% - 70% operated ones are died within 30 days after operation. Early diagnosis and follow-up is extremely important to decrease morbidity and mortality. The patients consulting with rupture must be taken to the operation without delay. What should be done if coronary artery disorder is detected in the patient whose AAA is ruptured and if the bypass is necessary? In our opinion, a decision must be made according to the patient’s clinical condition. As a result of our case, we thought repairing the abdominal aortic aneurysm necessitates the other comorbidites must be treated medically. We aimed to decrease the cardiac oxygen requirement by starting levosimendan and decline afterload. If the patient, whose coronary artery disorder is detected, is under risk and his overall condition is bad, we think that coronary bypass operation can be delayed.

Association Study of Single Nucleotide Polymorphisms on Chromosome 19q13 With Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a complex disorder in which environmental and genetic factors play a role in pathogenesis. Linkage to 2 adjacent loci on 19q13 in familiar AAA was previously demonstrated. We studied whether genetic variation within these regions predisposes to AAA. Common genetic variants in the described regions on 19q13 were analyzed using tag single nucleotide polymorphisms (SNPs) in a Dutch case-control population. Single nucleotide polymorphism genotyping was performed in a 2-stage approach. In stage 1, 615 SNPs were genotyped in 376 AAA patients and 648 controls. In stage 2, 8 SNPs of stage 1 with a P value < .015 were genotyped in a second independent cohort of 360 cases and 376 controls. No differences in allele frequencies were observed. Our findings suggest that there are no common AAA predisposing SNPs within the 19q13 loci. Hence, the genetic basis of familiar and sporadic AAA may differ.

Pharmacological therapy for patients with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a common and life-threatening disease characterized by progressive dilatation and rupture, and has a mortality rate of up to 90%. Surgical repair is recommended for large aneurysms, whereas small aneurysms are managed by ‘watchful waiting’. The recently introduced AAA screening programs reduce aneurysm-related mortality; however, aneurysm detection leads to psychological problems and a reduced quality of life of patients. The success of pharmacological therapy for AAA in small animals continues to provide insights into the pathogenetic mechanisms of this disease. As a result, medications, such as doxycycline, roxithromycin and statins, have been used to limit the growth of AAAs in small human studies with promising results. However, randomized trials with large numbers of patients and long follow-ups are required for the thorough investigation of safe and effective medical therapies. Control of cardiovascular risk factors, particularly smoking cessation, may result in a reduced growth of the AAA and improve overall patient care.

Blocking TNF-α Attenuates Aneurysm Formation in a Murine Model

Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This chronic infiltrate is predominately composed of macrophages and T lymphocytes. Activated macrophages produce a variety of cytokines, including TNF-alpha. Elevated levels of TNF-alpha were observed in patients with AAA, suggesting that TNF-alpha may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-alpha in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-alpha were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-alpha. These mice were resistant to aneurysm formation. Our results show that TNF-alpha deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-alpha plays a central role in regulating matrix remodeling and inflammation in the aortic wall leading to AAA. In addition, we investigated the pharmacological inhibition of AAA. A Food and Drug Administration-approved TNF-alpha antagonist, infliximab, inhibited aneurysm growth. Our data also show that infliximab treatment attenuated elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue. This study confirms that a strategy of TNF-alpha antagonism may be an important therapeutic strategy for treating AAA.