CEA vs. stent in patients with acute strokes: are they equally effective?

INTRODUCTION: Stroke is the 3rd leading cause of death worldwide with 15 million strokes annually. Extracranial carotid stenosis contributes to major stroke morbidity and mortality as a significant etiology of ischemic strokes. For acute stroke, in addition to optimal medical management, patients may be candidates for carotid endarterectomy and/or carotid stenting for secondary stroke reduction. This paper set out to review the data currently available regarding equivalency of the two intervention options. EVIDENCE ACQUISITION: A comprehensive literature review was performed through PubMed and other sources using the key words carotid endarterectomy, carotid artery stent, acute stroke, symptomatic carotid stenosis, flow reversal, TCAR. Studies which solely evaluated patients with asymptomatic disease were ineligible for the study. EVIDENCE SYNTHESIS: Review of landmark trials such as NASCET and CREST in addition to more recent studies demonstrates the effectiveness of surgical management with carotid endarterectomy of acute stroke. Carotid stenting has also been shown to have acceptable outcomes in certain patient populations. CONCLUSIONS: Carotid endarterectomy continues to demonstrate effectiveness and safety for management of acute stroke, while carotid stenting has limitations. Carotid artery stenting has been shown to be non-inferior in some patient populations, but more recent and future technologic developments may expand the potential acceptable patient selection criteria.

Management and outcomes of carotid artery extension of aortic dissections.

BACKGROUND: Aortic dissection (AD) is the most common aortic catastrophe. Carotid artery dissection due to extension of AD (CAEAD) is one severe complication of this condition. Despite years of refinement in the techniques for repair of AD, the optimal management strategy for CAEAD remains yet to be described. We hypothesized that CAEAD eventually resolves on antiplatelet therapy with a low but not insignificant risk of cerebrovascular accident (CVA). METHODS: This was a single-institution retrospective review of patients admitted with nontraumatic coincident aortic and carotid dissection between 2001 and 2013. RESULTS: CAEAD was present in 38 patients (24 men [53%]). The median age was 59.5 years (range, 25-85 years). A Stanford type A AD was diagnosed in 36 patients (95%). CVA or transient ischemic attack was identified in 11 patients (29%). Eight were potentially attributable to the carotid lesion. Two of these eight strokes resulted in death. Of the 11 CVAs and transient ischemic attacks, 8 were evident at presentation, 2 were diagnosed postoperatively during hospitalization, and 1 was diagnosed during early follow-up. Only one of these three postadmission strokes was attributable to the carotid lesion. Nonoperative management of aortic and carotid dissections was pursued in 9 patients (24%), 26 (68%) underwent open repair, and 4 (11%) had endovascular management of AD (2 thoracic endovascular aortic repair, 2 endovascular fenestrations), including 1 patient with a staged hybrid procedure (frozen elephant trunk). There were eight inpatient deaths (21%) and nine deaths in the follow-up period. Of the 30 patients who survived to discharge, 24 (80%) were managed with antiplatelet therapy. At a median follow-up of 14.5 months in 22 patients with follow-up computed tomography scans available, a minority of lesions had resolved, and only one CVA was reported. CONCLUSIONS: This study found that CAEAD was associated almost exclusively with type A AD, was typically unilateral, most often on the left, and usually persisted at follow-up. Many CAEAD patients presented with CVA and experienced significant early mortality. Notably, not all CVA events were attributable to the CAEAD. CVAs were not common after admission, and there appeared to be a low risk of new or subsequent stroke during follow-up with routine antiplatelet and antihypertensive therapy.

Long-term follow-up of blunt cerebrovascular injuries: Does time heal all wounds?

BACKGROUND: The short-term natural history of blunt cerebrovascular injuries (BCVIs) has been previously described in the literature, but the purpose of this study was to analyze long-term serial follow-up and lesion progression of BCVI. METHODS: This is a single institution's retrospective review of a prospectively collected database over four years (2009-2013). All patients with a diagnosis of BCVI by computed tomographic (CT) scan were identified, and injuries were graded based on modified Denver scale. Management followed institutional algorithm: initial whole-body contrast-enhanced CT scan, followed by CT angiography at 24 to 72 hours, 5 to 7 days, 4 to 6 weeks, and 3 months after injury. All follow-up imaging, medication management, and clinical outcomes through 6 months following injury were recorded. RESULTS: There were 379 patients with 509 injuries identified. Three hundred eighty-one injuries were diagnosed as BCVI on first CT (Grade 1 injuries, 126; Grade 2 injuries, 116; Grade 3 injuries, 69; and Grade 4 injuries, 70); 100 "indeterminate" on whole-body CT; 28 injuries were found in patients reimaged only for lesions detected in other vessels. Sixty percent were male, mean (SD) age was 46.5 (19.9) years, 65% were white, and 62% were victims of a motor vehicle crash. Most frequently, Grade 1 injuries were resolved at all subsequent time points. Up to 30% of Grade 2 injuries worsened, but nearly 50% improved or resolved. Forty-six percent of injuries originally not detected were subsequently diagnosed as Grade 3 injuries. Greater than 70% of all imaged Grade 3 and Grade 4 injuries remained unchanged at all subsequent time points. CONCLUSIONS: This study revealed that there are many changes in grade throughout the six-month time period, especially the lesions that start out undetectable or indeterminate, which become various grade injuries. Low-grade injuries (Grades 1 and 2) are likely to remain stable and eventually resolve. Higher-grade injuries (Grades 3 and 4) persist, many up to six months. Inpatient treatment with antiplatelet or anticoagulation did not affect BCVI progression. LEVEL OF EVIDENCE: Prognostic study, level III; therapeutic study, level IV.

Intact Toll-like receptor 9 signaling in neutrophils modulates normal thrombogenesis in mice.

BACKGROUND: Deletion of Toll-like receptor 9 (Tlr9) signaling, which is important for sterile inflammatory processes, results in impaired resolution of venous thrombosis (VT) in mice. The purpose of this study was to determine if deletion of Tlr9 affected sterile necrosis, apoptosis, and neutrophil extracellular trap (NET) production in VT. METHODS: Stasis and nonstasis murine models of VT were used in wild-type (WT) and Tlr9-/- mice, with assessment of thrombus size and determination of NETs, necrosis, and apoptosis markers. Anti-polymorphonuclear neutrophil (PMN) and antiplatelet antibody strategies were used to determine the cellular roles and their roles in WT and Tlr9-/- mice. RESULTS: At 2 days, stasis thrombi in Tlr9-/- mice were 62% larger (n = 6-10), with 1.4-fold increased uric acid levels, 1.7-fold more apoptotic cells, 2-fold increased citrullinated histones, 2-fold increased peptidylarginine deiminase 4 (PAD4), and 1.5-fold increased elastase and a 2.4-fold reduction in tissue factor pathway inhibitor compared with WT mice (all n = 4-7; P < .05). In contrast, the sizes of nonstasis thrombi were not significantly different in Tlr9-/- mice (n = 4-6), and they did not have elevated necrosis or NET markers. Stasis thrombus size was not reduced at the 2-day time point in WT or Tlr9-/- mice that received treatment with deoxyribonuclease I or in PAD4-/- mice, which are incapable of forming NETs. In Tlr9-/- mice undergoing PMN depletion (n = 8-10), stasis thrombus size was reduced 18% and was associated with 29-fold decreased citrullinated histones, 1.3-fold decreased elastase, and 1.5-fold increased tissue factor pathway inhibitor (all n = 6; P < .05). Last, platelet depletion (>90% reduction) did not significantly reduce stasis thrombus size in Tlr9-/- mice. CONCLUSIONS: These data suggest that the thrombogenic model affects Tlr9 thrombogenic mechanisms and that functional Tlr9 signaling in PMNs, but not in platelets or NETs, is an important mechanism in early stasis experimental venous thrombogenesis.

Ex vivo repair of renal artery aneurysms.

OBJECTIVE: Renal artery aneurysms (RAAs) are rare but remain challenging lesions when treatment is required. Endovascular techniques may be useful in selected, more proximal lesions with amenable morphology, but open surgical repair is often required for more distal, anatomically complex hilar RAAs that often have several branches and unfavorable anatomy. This study reviewed a single-center experience with ex vivo repair of 14 of these more complex, distal RAAs. METHODS: The records of 14 consecutive patients having ex vivo RAA repair between 1997 and 2013 were retrospectively reviewed. Demographic data, operative details, and blood pressure and renal function status were recorded. Graft patency was observed with renal duplex sonography. RESULTS: Fourteen hilar RAAs were repaired in 10 women and 4 men with a mean age of 54 years. Hypertension was present in 12 (86%). Preoperative renal dysfunction was present in two (14%). Aneurysm size averaged 2.9 cm. Six RAAs (43%) were symptomatic with flank or abdominal pain. Ex vivo repair was performed in all cases with use of saphenous vein for renal-renal bypass. No patient had pelvic autotransplantation or concomitant aortic reconstruction. Ex vivo RAA repair was technically successful in 12 cases; two patients required nephrectomy. Two patients with pre-existing renal insufficiency had improvement postoperatively, but hypertension was clinically unchanged in all patients. No patient required postoperative dialysis. Duplex sonography documented continued graft patency in the 12 technically successful cases during a mean follow-up of 19 months. CONCLUSIONS: Open ex vivo surgical repair with renal-renal bypass is a successful and durable treatment for complex distal RAAs that require repair. These procedures had low morbidity and mortality and an acceptable rate of renal function preservation. Blood pressure control in these patients did not change significantly after RAA repair.

Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury.

Deep-vein thrombosis (DVT) resolves via a sterile inflammatory response. Defining the inflammatory response of DVT may allow for new therapies that do not involve anticoagulation. Previously, we have shown that Toll-like receptor 9 (Tlr9) gene deleted mice had impaired venous thrombosis (VT) resolution. Here, we further characterise the role of Tlr9 signalling and sterile inflammation in chronic VT and vein wall responses. First, we found a human precedent exists with Tlr9+ cells present in chronic post thrombotic intraluminal tissue. Second, in a stasis VT mouse model, endogenous danger signal mediators of uric acid, HMGB-1, and neutrophil extracellular traps marker of citrullinated histone-3 (and extracellular DNA) were greater in Tlr9-/- thrombi as compared with wild-type (WT), corresponding with larger VT at 8 and 21 days. Fewer M1 type (CCR2+) monocyte/macrophages (MØ) were present in Tlr9-/- thrombi than WT controls at 8 days, suggesting an impaired inflammatory cell influx. Using bone marrow-derived monocyte (BMMØ) cell culture, we found decreased fibrinolytic gene expression with exposure to several endogenous danger signals. Next, adoptive transfer of cultured Tlr9+/+ BMMØ to Tlr9-/- mice normalised VT resolution at 8 days. Lastly, although the VT size was larger at 21 days in Tlr9-/- mice and correlated with decreased endothelial antigen markers, no difference in fibrosis was found. These data suggest that Tlr9 signalling in MØ is critical for later VT resolution, is associated with necrosis clearance, but does not affect later vein wall fibrosis. These findings provide insight into the Tlr9 MØ mechanisms of sterile inflammation in this disease process.

Lethal now or lethal later: The natural history of Grade 4 blunt cerebrovascular injury.

BACKGROUND: Grade 4 blunt cerebrovascular injury (BCVI4) has a known, significant rate of stroke. However, little is known about the natural history of BCVI4 and the pathophysiology of subsequent stroke formation. METHODS: A 4-year review of patients with BCVI4 at the R Adams Cowley Shock Trauma Center was performed. Rates of BCVI4-related stroke, stroke-related mortality, and overall mortality were calculated. The relationship of change in vessel characteristics and BCVI4-related stroke was examined, as was the mechanism of stroke formation. RESULTS: There were 82 BCVI4s identified, with 13 carotid artery (ICA) and 69 vertebral artery BCVI4s. BCVI4-related stroke rate was 2.9% in vertebral artery BCVI4 and 70% in ICA BCVI4 patients surviving to reimaging. Stroke mechanisms included embolic strokes, thrombotic strokes, and combined embolic and thrombotic strokes. Peristroke vessel recanalization and an embolic stroke mechanism were seen in 100% of ICA BCVI4-related strokes developing after admission. BCVI4-related stroke occurred within 10 hours of hospital admission in 67% of the patients with strokes. Contraindications to anticoagulation were present in most patients with BCVI4-related stroke developing after admission. CONCLUSION: Multiple etiologies of stroke formation exist in BCVI4. Early risk-benefit analysis for initiation of anticoagulation or antiplatelet agents should be performed in all patients with BCVI4, and the use of endovascular vessel occlusion should be considered in those with true contraindications to anticoagulation. However, more aggressive medical therapy may be needed to lessen BCVI4-related stroke development. LEVEL OF EVIDENCE: Prognostic study, level IV; therapeutic study, level V.

Initial screening test for blunt cerebrovascular injury: Validity assessment of whole-body computed tomography.

INTRODUCTION: Our whole-body computed tomography protocol (WBCT), used to image patients with polytrauma, consists of a noncontrast head computed tomography (CT) followed by a multidetector computed tomography (40- or 64- slice) that includes an intravenous, contrast-enhanced scan from the face through the pelvis. WBCT is used to screen for blunt cerebrovascular injury (BCVI) during initial CT imaging of the patient with polytrauma and allows for early initiation of therapy with the goal of avoiding stroke. WBCT has not been directly compared with CT angiography (CTA) of the neck as a screening tool for BCVI. We hypothesize that WBCT is a valid modality to diagnose BCVI compared with neck CTA, thus screening patients with polytrauma for BCVI and limiting the need for subsequent CTA. METHODS: A retrospective review of the trauma registry was conducted for all patients diagnosed with BCVI from June 2009 to June 2013 at our institution. All injuries, identified and graded on initial WBCT, were compared with neck CTA imaging performed within the first 72 hours. Sensitivity was calculated for WBCT by the use of CTA as the reference standard. Proportions of agreement also were calculated between the grades of injury for both imaging modalities. RESULTS: A total of 319 injured vessels were identified in 227 patients. On initial WBCT 80 (25%) of the injuries were grade I, 75 (24%) grade II, 45 (14%) grade III, 41 (13%) grade IV, and 58 (18%) were classified as indeterminate: 27 vertebral and 31 carotid lesions. Twenty (6%) of the 319 injuries were not detected on WBCT but identified on subsequent CTA (9 grade I, 7 grade II, 4 grade III); 6 vertebral and 14 carotid. For each vessel type and for all vessels combined, WBCT demonstrated sensitivity rates of over 90% to detect BCVI among the population of patients with at least one vessel injured. There was concordant grading of injuries between WBCT and initial diagnostic CTA in 154 (48% of all injuries). Lower grade injures were more discordant than higher grades (55% vs 13%, respectively; P < .001). Grading was upgraded 8% of the time and downgraded 25%. CONCLUSION: WBCT holds promise as a rapid screening test for BCVI in the patient with polytrauma to identify injuries in the early stage of the trauma evaluation, thus allowing more rapid initiation of treatment. In addition, in those patients with high risk for BCVI but whose WBCT results are negative for BCVI, neck CTA should be considered to more confidently exclude low-grade injuries.

Blunt cerebrovascular injury screening guidelines: what are we willing to miss?

BACKGROUND: Blunt cerebrovascular injury (BCVI) is reported to occur in approximately 2% of blunt trauma patients, with a stroke rate of up to 20%. Guidelines for BCVI screening are based on clinical and radiographic findings. We hypothesized that liberal screening of the neck vasculature, as part of initial computed tomographic (CT) imaging in blunt trauma patients with significant mechanisms of injury, identifies BCVI that may go undetected. METHODS: As per protocol, patients at risk for significant injuries undergo a noncontrast head CT scan followed by a multislice CT scan (40-slice or 64-slice) incorporating an intravenous contrast-enhanced pass from the circle of Willis through the pelvis (whole-body CT [WBCT] scan). The trauma registry was retrospectively reviewed, and all patients with BCVI from 2009 to 2012 were analyzed. Patients undergoing WBCT scan were then identified, and records were reviewed for BCVI indicators (skull base fracture, cervical spine injury, displaced facial fracture, mandible fracture, Glasgow Coma Scale score ≤ 8, flexion mechanism, hard signs of neck vascular injury, or focal neurologic deficit). RESULTS: Of 16,026 patients evaluated during the study period, 256 (1.6%) were diagnosed with BCVI. The population consisted of 185 patients with suspected BCVI after WBCT scan. One hundred twenty-nine patients (70%) had at least one indicator for BCVI screening, while 56 (30%) had no radiographic or clinical risk factors; 48 of the 56 patients underwent confirmatory CT angiography of the neck within 71 hours of initial WBCT scan, with 35 patients having 45 injuries. CONCLUSION: More liberalized screening for BCVI during initial CT imaging in trauma patients clinically judged to have sufficient mechanism is warranted. Using current BCVI screening guidelines leads to missed BCVI and risk of stroke. LEVEL OF EVIDENCE: Diagnostic study, level III.

Increased estrogen receptor alpha in experimental aortic aneurysms in females compared with males.

BACKGROUND: Estrogen receptor alpha (ERα) has been identified in the vessel wall, offering vasoprotective effects when upregulated. Estrogens are known to mediate the inflammatory milieu, and inflammation has long been associated with abdominal aortic aneurysm (AAA) formation. Therefore, it is theorized that increased estrogen receptor in females contributes to their relative resistance to AAAs. The objective of this study was to determine gender differences in ERα levels during experimental AAA formation. METHODS: Infrarenal aortas of male and female C57 mice (n = 18 and n = 16, respectively) were infused with 0.4% elastase. Diameters were measured at days 0 and 14. Aortic messenger RNA expression of ERα was determined on day 3 by reverse transcription-polymerase chain reaction, whereas ERα protein levels were measured via Western blot. Immunohistochemistry using rabbit antibody for ERα was performed on day 14 samples and quantified. Zymography was done for matrix metalloproteinases (MMP)2 and 9 activity levels. Samples of human AAAs were collected and Western blot performed. Data were compared for significance using a student t-test. RESULTS: Infrarenal aortic diameter increased in elastase-perfused males (ME) by 80% at 14 days after perfusion, whereas females (FE) increased by only 35% (P = 0.0012). FE had ×10 greater ERα messenger RNA expression compared with ME at day 3 (P = 0.003). Similarly, ERα protein levels were 100% higher in FE compared with those in ME on day 14 (P = 0.035). ERα protein levels were 80% higher in female human patients with AAA than those in their male counterparts (P = 0.029). ERα visualized via immunohistochemistry was 1.5 fold higher in FE than ME (P = 0.029). MMP2 and 9 activity levels were decreased in female compared with male aortas. CONCLUSIONS: This study demonstrates an increase in aortic wall ERα in females compared with males that correlates inversely with MMP activity and AAA formation. These findings, coupled with observations that exogenous estrogen inhibits AAA formation in males, further suggest that estrogen supplementation may be important to prevent AAA formation and growth.

Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling.

OBJECTIVE: Deep vein thrombosis (VT) can result in vein wall injury, which clinically manifests as post-thrombotic syndrome. Postinjury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7)-mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7. APPROACH AND RESULTS: CCR7(-/-) and C57BL/6 wild-type mice had inferior vena cava VT induced by nonstasis or stasis mechanisms. In both models, VT size was largest at day 1 and trended down by day 21, and CCR7(+) cells peaked at day 8 in wild-type mice. No significant differences in VT resolution were found in CCR7(-/-) as compared with wild type in either model. In the nonstasis VT model, vein wall changes consistent with fibrotic injury were evidenced by significant increases in collagen I, III, matrix metalloproteinase 2, and transforming growth factor-ß gene expression, increases in α-smooth muscle actin and fibroblast specific protein-1 antigen, and total collagen at 8 days. Correspondingly, SM22α and fibroblast specific protein-1, but not DDR2(+) cells, were increased at 8 days. Early wild-type thrombus exposure inhibited profibrotic gene expression in CCR7(-/-) in ex vivo vein wall culture. Bone marrow chimera experiments further showed that circulating CCR7(+) leukocytes partially rescued midterm profibrotic changes in CCR7(-/-) mice. In human histological sections of chronic thrombosed femoral veins, CCR7(+) cells were present in the fibrotic areas. CONCLUSIONS: Post-thrombotic vein wall remodeling is impaired in CCR7(-/-) mice, with a profibrotic phenotype, is dependent on the thrombotic mechanism, and is mediated by circulating CCR7(+) cells. Unlike other postinjury fibrotic responses, CCR7(+) signaling may be important for positive vein wall remodeling after VT.

Phosphorylation of AKT and abdominal aortic aneurysm formation.

It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.

Development of a novel murine model of aortic aneurysms using peri-adventitial elastase.

BACKGROUND: Our aim was to establish a novel model of abdominal aortic aneurysms (AAA) in mice using application of peri-adventitial elastase. METHODS: C57BL/6J male mice underwent infrarenal peri-adventitial application of either (1) sodium chloride (control; n = 7), (2) porcine pancreatic elastase (PPE; n = 14), or (3) PPE and doxycycline (PPE + doxycycline 200 mg/kg; n = 11) for 14 days. Aortas were analyzed by video micrometry, immunohistochemistry, qualitative polymerase chain reaction, and zymography. Groups underwent Mann-Whitney U comparisons. RESULTS: At day 14 compared with baseline, control animals had minimal aortic dilation, whereas fusiform aneurysms were seen in PPE (control, 20 ± 3%; PPE, 82 ± 15%; P ≤ .003). Doxycycline abrogated aneurysm formation (PPE, 82 ± 15%; PPE + doxycycline, 37 ± 10%; P ≤ .03). Compared with control and PPE + doxycycline, immunohistochemistry demonstrated greater elastin fiber degradation, macrophage infiltration, and matrix metalloproteinase-9 expression in PPE. Ki-67 and cleaved caspase-3 were lower in control versus PPE. The loss of smooth muscle marker expression seen with PPE was preserved in PPE + doxycycline. Zymography confirmed that both MMP-2 and -9 were more active in PPE than PPE + doxycycline. CONCLUSION: Peri-adventitial application of elastase is a simple, reproducible in vivo model of aneurysm formation leading to consistent infrarenal aortic aneurysm development by day 14, with inflammatory cell infiltration and MMP upregulation. Doxycycline inhibits AAA progression in this model via limiting matrix degradation and preserving differentiated smooth muscle cells.

Differential gender- and species-specific formation of aneurysms using a novel method of inducing abdominal aortic aneurysms.

BACKGROUND: The objective of this study was to test a novel model of inducing abdominal aortic aneurysms (AAAs) in different mouse strains and genders. MATERIALS AND METHODS: Male and female C57BL/6 and B6129 mice (n = 5 per group) underwent periaortic dissection and porcine pancreatic elastase (30 µL) or inactivated elastase application (5 min) to the aorta. Aortic measurements were taken on days 0 and 14. Aortic samples were analyzed for histology and zymography for matrix metalloproteinase (MMP) activity. Comparison statistics were performed using unpaired t-test. RESULTS: AAA phenotype (50% aortic increase) occurred in external elastase-treated males (100%) and females (90%). No control animals developed AAAs. The aortic diameter was larger in C57BL/6 and B6129 elastase-treated versus control males (P = 0.0028 and P < 0.0001, respectively) and females (P < 0.0001 and P = 0.0458, respectively). Histology verified phenotype via disrupted internal elastic laminae. Macrophage counts in elastase-treated animals were >6-fold higher than in controls (all groups significant). MMP9 activity was greater in elastase-treated males and females in C57BL/6 (P = 0.0031, P = 0.0004) and B6129 (P = 0.025, P = 0.2) mice; MMP2 activity was greater in C57BL/6 versus B6129 male elastase-treated mice. CONCLUSIONS: This rodent model produced AAAs in both genders and strains of mice. This model is simple, has little variability, and occurs in the infrarenal aorta, substantiating the external elastase model for future studies.

Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model.

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

Increased JNK in males compared with females in a rodent model of abdominal aortic aneurysm.

BACKGROUND: In humans, there is a 4:1 male:female ratio in the incidence of abdominal aortic aneurysms (AAAs). c-Jun-N-terminal kinase (JNK) is an important upstream regulator of several enzymes involved in AAA formation, including the matrix metalloproteinases (MMPs). The purpose of this study was to determine if there is a gender difference between males and females in JNK during AAA formation. MATERIALS AND METHODS: Male and female C57/B6 mice underwent aortic perfusion with elastase or heat inactivated elastase with aortas harvested at d 3 and 14 for phenotype determination, RT-PCR, Western blot, and zymography. Additionally, in vitro experiments using siRNA were conducted to define JNK regulation of matrix metalloproteinases (MMPs). A t-test was used to compare between groups. RESULTS: Males formed larger AAAs at d 14 compared with females (P < 0.001), with significantly higher levels of JNK1 protein, proMMP9, proMMP2, and active MMP2. At d 3, males had more JNK1 mRNA, protein, and MMP activity. Knockdown of JNK 1 or 2 in vitro decreased MMP activity, while knockdown of JNK 1 and 2 together blocked all MMP activity. CONCLUSION: Alterations in JNK between genders is partially responsible for the differential rates of experimental AAA formation, likely through differential regulation of MMPs.

Graft infection after endovascular abdominal aortic aneurysm repair.

INTRODUCTION: Although the natural history and management of infected open abdominal aortic aneurysm (AAA) repair is well described, only sporadic case reports have described the fate of patients with infected endografts placed in the abdominal aorta. The present study describes a tertiary referral center's experience with infected endovascular aneurysm repairs (EVARs). METHODS: The medical records of 1302 open and endovascular aortic procedures were queried from January 2000 to January 2010. The cases were reviewed for prior aortic procedures, prosthetic implants, and etiology of current open procedure. Demographics, operative details, and perioperative courses were documented. RESULTS: Nine patients (1 woman) with a mean age of 71 years had an EVAR that later required an open procedure for explantation and surgical revision for suspected infection. All grafts were explanted through a midline transperitoneal approach, with a mean time to explant of 33 months. The explanted endografts included 4 Zenith (Cook, Bloomington, Ind), 2 Ancure (Endovascular Technologies, Menlo Park, Calif), 2 Excluders (Gore, Flagstaff, Ariz), and 1 AneuRx (Medtronic, Minneapolis, Minn). Eight of the nine original EVARs were performed at other hospitals; 1 patient had EVAR and open explant at the University of Michigan. All patients had preoperative computed tomography scans, except one who was transferred in extremis with a gastrointestinal hemorrhage. Three patients also had a tagged leukocyte scan, and two had magnetic resonance imaging to further reinforce the suspicion of infection before explantation and bypass planning. Rifampin-soaked Hemashield (Boston Scientific) in situ grafts were used in four patients, with extra-anatomic (axillary-bifemoral) bypass used in the other five. The in situ group had no positive preoperative or postoperative cultures, with the exception of the unstable patient who died the day of surgery. For the other five patients, positive tissue cultures were found for Bacteroides, Escherichia coli, coagulase-negative Staphylococcus, Streptococcus, and Candida. Three patients were found to have aortic-enteric fistula, two of whom died before discharge from the hospital. The remaining seven survived to discharge. Average length of stay was 22 days, with a median follow-up of 11 months. CONCLUSION: This series of infected EVARs is the largest group of infected AAA endografts reported to date. Because EVAR of AAAs is presently the most common method of repair, development of endograft infection, while rare, can be managed with acceptable mortality rates. Patients presenting with aortic-enteric fistula after EVAR appear to have a more virulent course.