ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Neurofibromin 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation.

Objective- The goal of this study was to determine the role of ZFP148 (zinc-finger protein 148) in aneurysm formation. Approach and Results- ZFP148 mRNA expression increased at day 3, 7, 14, 21, and 28 after during abdominal aortic aneurysm formation in C57BL/6 mice. Loss of ZFP148 conferred abdominal aortic aneurysm protection using ERTCre+ ZFP148 flx/flx mice. In a third set of experiments, smooth muscle-specific loss of ZFP148 alleles resulted in progressively greater protection using novel transgenic mice (MYH [myosin heavy chain 11] Cre+ flx/flx, flx/wt, and wt/wt). Elastin degradation, LGAL3, and neutrophil staining were significantly attenuated, while α-actin staining was increased in ZFP148 knockout mice. Results were verified in total cell ZFP148 and smooth muscle-specific knockout mice using an angiotensin II model. ZFP148 smooth muscle-specific conditional mice demonstrated increased proliferation and ZFP148 was shown to bind to the p21 promoter during abdominal aortic aneurysm formation. ZFP148 smooth muscle-specific conditional knockout mice also demonstrated decreased apoptosis as measured by decreased cleaved caspase-3 staining. ZFP148 bound smooth muscle marker genes via chromatin immunoprecipitation analysis mediated by NF-1 (neurofibromin 1) promote histone H3K4 deacetylation via histone deacetylase 5. Transient transfections and chromatin immunoprecipitation analyses demonstrated that NF-1 was required for ZFP148 protein binding to smooth muscle marker genes promoters during aneurysm formation. Elimination of NF-1 using shRNA approaches demonstrated that NF-1 is required for binding and elimination of NF-1 increased BRG1 recruitment, the ATPase subunit of the SWI/SWF complex, and increased histone acetylation. Conclusions- ZFP148 plays a critical role in multiple murine models of aneurysm formation. These results suggest that ZFP148 is important in the regulation of proliferation, smooth muscle gene downregulation, and apoptosis in aneurysm development.

Staged hybrid repair of extensive thoracoabdominal aortic aneurysms secondary to chronic aortic dissection.

OBJECTIVE: Many patients with aortic dissection develop Crawford extent I or II thoracoabdominal aortic aneurysms (TAAA). Because open repair is associated with a high morbidity and mortality, hybrid approaches to TAAA repair are emerging. In this study, we evaluated the midterm outcomes and aortic remodeling of a hybrid technique that combines proximal thoracic endovascular aneurysm repair (TEVAR), followed by staged distal open thoracoabdominal repair for patients with Crawford extent I or II TAAAs secondary to chronic aortic dissection. METHODS: We identified 19 patients with Crawford extent I (n = 1) or extent II (n = 18) TAAAs secondary to chronic aortic dissection who underwent a staged hybrid repair from 2007 to 2014 at our institution. Nine patients had previous open ascending aortic surgery for type I aortic dissection. Stage 1 TEVAR was performed via percutaneous (n = 8), femoral cutdown (n = 8), or iliac exposure (n = 3). The left subclavian artery was covered in nine patients and revascularized in eight patients using carotid-subclavian bypass (n = 7) or laser fenestration (n = 1). Stage 2 open repair was performed a median of 18 weeks later with partial cardiopulmonary bypass via left femoral arterial and venous cannulation for visceral and lower body perfusion. The open thoracoabdominal graft was anastomosed proximally in an end to end fashion with the endograft. We then assessed surgical morbidity and mortality, midterm survival, and freedom from reintervention. Aortic remodeling was measured and change in maximum aortic and false lumen diameter at last follow-up (median, 3 years) from baseline was assessed. RESULTS: There were no deaths, strokes, or chronic renal failure in this cohort. After stage 1 TEVAR, three patients required repeat intervention for endoleak (type Ia, n = 1; type Ib, n = 1; type II, n = 1) before open repair. After stage 2 open repair, there was a single delayed permanent paralysis 2 weeks after discharge. At a median 3-year follow-up (range, 6 months-6.2 years), there were no deaths, neurologic events, endoleaks, or TAAA reinterventions. Complete false lumen thrombosis occurred in 100% of the patients, with maximum false lumen diameter decreasing from 34.3 ± 15.3 mm to 13.2 ± 12.0 mm (P < .01) and total aortic diameter decreasing from 60.2 ± 9.0 mm to 49.4 ± 9.6 mm (P < .01). CONCLUSIONS: Staged hybrid TAAA repair, using a combination of proximal TEVAR with open distal repair, can be performed using established endovascular skills and technology coupled with traditional open aortic surgical techniques, with low surgical morbidity and mortality. In the midterm, staged hybrid TAAA repair was associated favorable survival, aortic remodeling, and freedom from reintervention.

Inhibition of interleukin-1ß decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

BACKGROUND: Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1ß (IL-1ß) is undetermined. METHODS AND RESULTS: IL-1ß protein was measured in human TAAs and control aortas, and IL-1ß protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6±24.7% compared with 14.4±8.2% for WT saline control (P<0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1ß expression. Next, TAAs were induced in mice deficient of IL-1ß (IL-1ß knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1ß and IL-1R significantly decreased thoracic aortic dilation (IL-1ß knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1ß knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1ß and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2±15.5% versus anakinra: 68.3±19.2%; P<0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1±18.6% versus anakinra treatment: 59.7±25.7%; P=0.01). CONCLUSIONS: Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1ß decreased TAA formation and progression, indicating that IL-1ß may be a potential target for TAA treatment.

Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury.

Outcomes for lung transplantation are the worst of any solid organ, and ischemia-reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-α), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI.

B2 cells suppress experimental abdominal aortic aneurysms.

Recent reports of rupture in patients with abdominal aortic aneurysm (AAA) receiving B-cell depletion therapy highlight the importance of understanding the role of B cells (B1 and B2 subsets) in the development of AAA. We hypothesized that B2 cells aggravate experimental aneurysm formation. The IHC staining revealed infiltration of B cells in the aorta of wild-type (C57BL/6) mice at day 7 after elastase perfusion and persisted through day 21. Quantification of immune cell types using flow cytometry at day 14 showed significantly greater infiltration of mononuclear cells, including B cells (B2: 93% of total B cells) and T cells in elastase-perfused aortas compared with saline-perfused or normal aortas. muMT (mature B-cell deficient) mice were prone to AAA formation similar to wild-type mice in two different experimental AAA models. Contradicting our hypothesis, adoptive transfer of B2 cells suppressed AAA formation (102.0% ± 7.3% versus 75.2% ± 5.5%; P < 0.05) with concomitant increase in the splenic regulatory T cell (0.24% ± 0.03% versus 0.92% ± 0.23%; P < 0.05) and decrease in aortic infiltration of mononuclear cells. Our data suggest that B2 cells constitute the largest population of B cells in experimental AAA. Furthermore, B2 cells, in the absence of other B-cell subsets, increase splenic regulatory T-cell population and suppress AAA formation.

Aromatase is required for female abdominal aortic aneurysm protection.

OBJECTIVE: The protective effects of female gender on the development of abdominal aortic aneurysms (AAAs) have been attributed to anti-inflammatory effects of estrogen. Estrogen synthesis is dependent on the enzyme aromatase, which is located both centrally in the ovaries and peripherally in adipose tissue, bone, and vascular smooth muscle cells. It is hypothesized that deletion of aromatase in both ovarian and peripheral tissues would diminish the protective effect of female gender and would be associated with increased aortic diameter in female mice. METHODS: Male and female 8- to 10-week-old mice with aromatase (wild type: WT) and without aromatase (ArKO) underwent elastase aortic perfusion with aortic harvest 14 days following. For the contribution of central and peripheral estrogen conversion to be evaluated, female WT mice were compared with female WT and ArKO mice that had undergone ovariectomy (ovx) at 6 weeks followed by elastase perfusion at 8 to 10 weeks. At aortic harvest, maximal aortic dilation was measured and samples were collected for immunohistochemistry and protein analysis. Serum was collected for serum estradiol concentrations. Groups were compared with analysis of variance. Human and mouse AAA cross sections were analyzed with confocal immunohistochemistry for aromatase, smooth muscle markers, and macrophage markers. RESULTS: Female WT mice had significant reduction in aortic dilation compared with male WT mice (F WT, 51.5% ± 15.1% vs M WT, 78.7% ± 14.9%; P < .005). The protective effects of female gender were completely eliminated with deletion of aromatase (F ArKO, 82.6% ± 13.8%; P < .05 vs F WT). Ovariectomy increased aortic dilation in WT mice (F WT ovx, 70.6% ± 11.7%; P < .05 vs F WT). Aromatase deletion with ovariectomy further increased aortic dilation compared with WT ovx mice (F ArKO ovx, 87.3% ± 14.7%, P < .001 vs F WT and P < .05 vs F WT ovx). Accordingly, female ArKO ovx mice had significantly higher levels of the proinflammatory cytokines monocyte chemoattractant protein 1 and interleukin-1ß and were associated with increased macrophage staining and decreased elastin staining. Regarding serum hormone levels, decreasing estradiol levels correlated with increasing aortic diameter (R = -0.565; P < .01). By confocal immunohistochemistry, both human and mouse AAA smooth muscle cells (smooth muscle α-actin positive) and macrophages (CD68 positive or Mac-2 positive) expressed aromatase. CONCLUSIONS: The protective effect of female gender on AAAs is due to estrogen synthesis and requires the presence of both ovarian and extragonadal/peripheral aromatase. Peripheral estrogen synthesis accounts for roughly half of the protective effect of female gender. If peripheral aromatase could be targeted, high levels of local estrogen could be produced and may avoid the side effects of systemic estrogen.

Exposure to Macaque Monkey Bite.

BACKGROUND: The herpes B virus is a zoonotic agent that is endemic among macaque monkeys only, but can cause fatal encephalomyelitis in humans. CASE REPORT: A 26-year-old female presented to a U.S. emergency department after being bitten by a wild macaque monkey. The emergency medicine team administered rabies immunoglobulin and rabies vaccine. The team also prescribed acyclovir for prophylactic coverage against herpes B, a deadly zoonotic agent that is endemic among macaque monkeys. A discussion of background, exposure, transmission, symptoms, treatment for herpes B, including latest data available, literature, and Centers for Disease Control and Prevention guidelines are included. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Zoonotic exposures can cause infectious diseases, which are unfamiliar and deadly. The emergency physician's knowledge of the association between the deadly herpes B infection and wild macaque monkey may expedite treatment and be instrumental in patient morbidity and survival.

KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation.

BACKGROUND: KLF4 mediates inflammatory responses after vascular injury/disease; however, the role of KLF4 in abdominal aortic aneurysms (AAAs) remains unknown. The goals of the present study were to (1) determine the role of KLF4 in experimental AAA; and (2) determine the effect of KLF4 on smooth muscle (SM) cells in AAAs. METHODS AND RESULTS: KLF4 expression progressively increased at days 3, 7, and 14 after aortic elastase perfusion in C57BL/6 mice. Separately, loss of a KLF4 allele conferred AAA protection using ERTCre+ KLF4 flx/wt mice in the elastase AAA model. In a third set of experiments, SM-specific loss of 1 and 2 KLF4 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt) in the elastase AAA model compared with control. Elastin degradation, MAC2, and cytokine production (MCP1, tumor necrosis factor-α, and interleukin-23) were significantly attenuated, whereas α-actin staining was increased in KLF4 knockout mice versus controls. Results were verified in global KLF4 and SM-specific knockout mice using an angiotensin II model of aneurysm formation. KLF4 inhibition with siRNA attenuated downregulation of SM gene expression in vitro, whereas in vivo studies demonstrated that KLF4 binds to promoters of SM genes by chromatin immunoprecipitation analysis. Finally, human aortic aneurysms demonstrated significantly higher KLF4 expression that was localized to SM cells. CONCLUSIONS: KLF4 plays a critical role in aortic aneurysm formation via effects on SM cells. These results suggest that KLF4 regulates SM cell phenotypic switching and could be a potential therapeutic target for AAA disease.

Dietary phytoestrogens inhibit experimental aneurysm formation in male mice.

BACKGROUND: The purpose of these experiments was to test the hypothesis that dietary phytoestrogens would diminish experimental aortic aneurysm formation. MATERIALS AND METHODS: Six-wk-old C57BL/6 mice were divided into groups, fed either a diet with minimal phytoestrogen content or a regular commercial rodent diet with high phytoestrogen content for 2 wk. At the age of 8 wk, aortic aneurysms were induced by infusing the isolated infrarenal abdominal aorta with 0.4% elastase for 5 min. Mice were recovered and the diameter of the infused aorta was measured at postoperative days 3, 7, and 14. Abdominal aorta samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Blood samples were also collected to determine serum phytoestrogens and estradiol levels. Multiple-group comparisons were done using an analysis of variance with post hoc Tukey tests. RESULTS: Compared with mice on a minimal phytoestrogen diet, mice on a regular rodent diet had higher levels of serum phytoestrogens (male, 1138 ± 846 ng/dL; female, 310 ± 295 ng/dL). These serum phytoestrogen levels were also much higher than their own endogenous estradiol levels (109-fold higher for males and 35.5-fold higher for females). Although aortic diameters of female mice were unaffected by the phytoestrogen concentration in the diets, male mice on the regular rodent diet (M+ group) developed smaller aortic aneurysms than male mice on the minimal phytoestrogen diet (M- group) on postoperative day 14 (M+ 54.8 ± 8.8% versus M- 109.3 ± 37.6%; P < 0.001). During aneurysm development (postoperative days 3 and 7), there were fewer neutrophils, macrophages, and lymphocytes in the aorta from the M+ group than from the M- group. Concentrations of multiple proinflammatory cytokines (matrix metalloproteinases [MMPs]; interleukin 1ß [IL-1ß]; IL-6; IL-17; IL-23; monocyte chemoattractant protein-1; regulated on activation, normal T cell expressed and secreted; interferon γ; and tumor necrosis factor α) from aortas of the M+ group were also lower than those from the aortas of the M- group. Zymography also demonstrated that the M+ group had lower levels of aortic MMP-9s than the M- group on postoperative day 14 (P < 0.001 for pro-MMP-9, P < 0.001 for active MMP-9). CONCLUSIONS: These results suggest that dietary phytoestrogens inhibit experimental aortic aneurysm formation in male mice via a reduction of the inflammatory response in the aorta wall. The protective effect of dietary phytoestrogens on aneurysm formation warrants further investigation.

Genetic and pharmacologic disruption of interleukin-1ß signaling inhibits experimental aortic aneurysm formation.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1ß (IL-1ß) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment. METHODS AND RESULTS: IL-1ß mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1ß (IL-1ß knockout [KO]) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1ß KO and 52.5±4.6% for IL-1R KO, compared with 89.4±4.0% for WT mice (P<0.005). Correspondingly, IL-1ß KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=-0.676; P<0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with control mice. CONCLUSIONS: IL-1ß is critical for AAA initiation and progression, and IL-1ß neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1ß signaling offers a novel pathway for AAA treatment.

Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment.

BACKGROUND: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that CD4+ T-cell-produced IL-17 modulates inflammation and smooth muscle cell activation, leading to the pathogenesis of AAA and that human mesenchymal stem cell (MSC) treatment can attenuate IL-17 production and AAA formation. METHODS AND RESULTS: Human aortic tissue demonstrated a significant increase in IL-17 and IL-23 expression in AAA patients compared with control subjects as analyzed by RT-PCR and ELISA. AAA formation was assessed in C57BL/6 (wild-type; WT), IL-23(-/-) or IL-17(-/-) mice using an elastase-perfusion model. Heat-inactivated elastase was used as control. On days 3, 7, and 14 after perfusion, abdominal aorta diameter was measured by video micrometry, and aortic tissue was analyzed for cytokines, cell counts, and IL-17-producing CD4+ T cells. Aortic diameter and cytokine production (MCP-1, RANTES, KC, TNF-α, MIP-1α, and IFN-γ) was significantly attenuated in elastase-perfused IL-17(-/-) and IL-23(-/-) mice compared with WT mice on day 14. Cellular infiltration (especially IL-17-producing CD4+ T cells) was significantly attenuated in elastase-perfused IL-17(-/-) mice compared with WT mice on day 14. Primary aortic smooth muscle cells were significantly activated by elastase or IL-17 treatment. Furthermore, MSC treatment significantly attenuated AAA formation and IL-17 production in elastase-perfused WT mice. CONCLUSIONS: These results demonstrate that CD4+ T-cell-produced IL-17 plays a critical role in promoting inflammation during AAA formation and that immunomodulation of IL-17 by MSCs can offer protection against AAA formation.

Association of race and socioeconomic status with the use of endovascular repair to treat thoracic aortic diseases.

OBJECTIVE: Descending thoracic aortic diseases may be treated with either open thoracic aortic repair or thoracic endovascular aortic repair (TEVAR). Previous studies have demonstrated that race and socioeconomic status (SES) affect access to care and treatment allocation in vascular surgery. We hypothesized that racial minorities and lower SES patients have decreased propensity to have their thoracic aortic disease treated with TEVAR. METHODS: Weighted discharge records for patients who underwent either open thoracic aortic repair or TEVAR between 2005 and 2008 were evaluated using the Nationwide Inpatient Sample. Patient records were stratified by therapeutic intervention (open repair vs TEVAR). Differences in baseline comorbidities, race, and SES were compared. To account for the effects of comorbidities and other factors, hierarchical logistic regression modeling was used to determine the likelihood for TEVAR performance based on differences in patients' race and SES. RESULTS: A total of 60,784 thoracic repairs were analyzed, the majority (79.4%) of which were open repairs. The most common race was white (78.2%), followed by black (9.1%), Hispanic (5.7%), Asian or Pacific Islander (2.9%), and Native American (0.7%). Patients were divided into quartiles according to SES with 20.6% of patients in the lowest SES quartile, 24.3% in the second quartile, 26.4% in the third quartile, and 28.8% in the highest SES quartile. Indications for treatment were similar for both treatment groups. After adjusting for multiple patient and hospital factors, race and SES were significantly associated with treatment modality for thoracic aortic disease. Black, Hispanic, and Native American populations had increased adjusted odds ratios of TEVAR performance compared with white patients. Similarly, lower SES correlated with increased use of TEVAR. CONCLUSIONS: Contrary to our initial hypothesis, racial minorities (Black, Hispanic, and Native American) and patients with lower median household incomes have a greater association with the performance for TEVAR after accounting for patient comorbid disease, indication for treatment, payer status, and hospital volume. These results indicate that traditional racial disparities do not persist in TEVAR allocation.

Transient paralysis from carbon dioxide angiography in a patient after four-vessel endovascular thoracoabdominal aortic aneurysm repair.

Contrast angiography with carbon dioxide (CO2) is frequently used in patients with renal dysfunction or iodinated contrast allergies, as CO2 is nonallergenic, nontoxic, and rapidly absorbed in the blood. However, when delivered intra-arterially, there is a possibility that CO2 may create a vapor lock with resultant transient ischemia. We describe a case of suspected CO2 embolus to the iliolumbar artery after iliac artery stenting resulting in immediate loss of bilateral lower extremity motor and sensory function. After placement of a spinal drain and elevation of mean arterial blood pressure, the patient had complete return of sensation with improvement in motor function.

Staged hybrid approach using proximal thoracic endovascular aneurysm repair and distal open repair for the treatment of extensive thoracoabdominal aortic aneurysms.

OBJECTIVE: Repair of patients with extent I and II thoracoabdominal aortic aneurysms (TAAAs) is associated with significant morbidity and mortality, whereas repair of more distal extent III and IV TAAAs has a lower risk of paraplegia and death. Therefore, we describe an approach using thoracic endovascular aneurysm repair (TEVAR) as the index operation to convert extent I and II TAAAs to extent III and IV TAAAs amenable to subsequent open aortic repair to minimize patient risk. METHODS: Between July 2007 and March 2012, 10 staged hybrid operations were performed to treat one extent I and nine extent II TAAAs. Aortic aneurysm pathology included five chronic type B dissections, three acute type B dissections, and two penetrating aortic ulcers. Initially, the proximal descending thoracic aorta was repaired with TEVAR for coverage of the most proximal fenestration or penetrating ulcer, with seven elective and three emergent repairs. Interval open distal aortic replacement was performed in a short-term planned setting or for progressive dilation of the distal aortic segment. In the open repair, the proximal end of the graft was sewn directly to the distal end of the TEVAR and outer wall of the aorta. RESULTS: Average patient age was 48 years, and 60% were men. Risk factors included hypertension (80%), current tobacco use (50%), and Marfan syndrome (30%). Complications after TEVAR included type IA (n=1) and type II (n=3) endoleaks, pleural effusions (n=3), and acute kidney injury (n=1). Three patients required endovascular reinterventions. In patients with dissection, persistent filling of the false lumen was common and associated with distal thoracic aortic dilation. Complications of open repair included acute kidney injury in two patients, but no cardiac, pulmonary, or neurologic morbidity. Median time between TEVAR and open repair was 14 weeks. Most importantly, no deaths or neurologic deficits occurred after either procedure during a median follow-up of 35 weeks. CONCLUSIONS: A staged hybrid approach to extensive TAAAs combining proximal TEVAR, followed by interval open distal TAAA repair, is safe and appears to be an effective alternative to traditional open repair. This approach may decrease the significant morbidity associated with single-stage open extent I and II TAAA repairs and may be applicable to multiple TAAA etiologies.

Greater saphenous vein evaluation from computed tomography angiography as a potential alternative to conventional ultrasonography.

OBJECTIVE: Autologous greater saphenous vein (GSV) graft is frequently used as a conduit during arterial bypass. Preoperative vein mapping has been traditionally used to assess conduit adequacy and define GSV anatomy, thereby decreasing operative time and reducing wound complications. The purpose of this study was to determine whether GSV mapping using computed tomography angiography (CTA) closely correlated with that of traditional duplex ultrasonography (US). METHODS: From August 2009 through June 2011, 88 limbs from 51 patients underwent CTA of the lower extremities for the purpose of defining arterial anatomy with concurrent US for preoperative vein mapping. GSV diameters were measured by two blinded reviewers on CTA (both antero-posterior [AP] and lateral dimensions) and compared with US-based measurements at levels of the proximal thigh, mid-thigh, knee, mid-calf, and ankle. CTA and US measurements were compared at each anatomic level using linear regression. Statistical analysis was performed using SPSS software. Charge reduction was calculated based on technical and professional fees for each imaging study. RESULTS: GSV diameter sequentially decreased from the proximal thigh to the mid-calf and then increased to the ankle as measured by CTA and US. CTA-based measurements of the GSV significantly correlated with US GSV diameters (R = 0.927 [lateral dimension], 0.922 [AP dimension]; P < .005). The strongest degree of correlation occurred in measurements at the proximal thigh, followed by the mid-thigh, mid-calf, knee, and ankle. GSV measurement by CTA was over 90% sensitive and accurate for detecting appropriate GSV diameter for bypass (diameter >2.0 mm). Eliminating preoperative US vein mapping for the study patients at our institution would have resulted in charge reductions of $49,316 over the study period. CONCLUSIONS: Indirect venography by CTA correlates well with US for GSV mapping in the lower extremity and offers significant reduction in imaging-related preoperative charges. CTA is sensitive and accurate for detecting GSVs that are appropriate for bypass. Furthermore, CTA allows AP and lateral evaluation of the GSV throughout its anatomic course. As CTA is often performed prior to arterial bypass, indirect evaluation of the GSV using preoperative CTA should be considered a promising alternative to the use of US.

Interleukin-6 Receptor Inhibition Prevents Descending Thoracic Aortic Aneurysm Formation.

BACKGROUND: Thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA) represent related but distinct disease processes. Interleukin-6 (IL-6) is known to be significantly upregulated in human TAA and AAA. We hypothesize that loss of IL-6 is protective in experimental TAA and AAA. METHODS: Murine TAAs or AAAs were created using a novel model in C57/B6 mice by treating the intact aorta with elastase. Cytokine profiles were analyzed with antibody arrays (n = 5 per group). Separately, to determine the role of IL-6, thoracic (n = 7) or abdominal (n = 7) aortas of wild type mice and IL-6 knockout (KO) mice were treated with elastase. Additionally, thoracic animals treated with either the IL-6 receptor antagonist tocilizumab (n = 8) or vehicle (n = 5). Finally, human TAA and AAA were analyzed with human cytokine array. RESULTS: Elastase treatment of thoracic aortas yielded dilation of 86.8% ± 9.6%, and abdominal aortas produced dilation of 85.6% ± 16.2%. Murine IL-6, CXCL13, and matrix metalloproteinase-9 were significantly elevated in TAA compared with AAA (p = 0.004, 0.028, and 0.001, respectively). The IL-6KO mice demonstrated significantly smaller TAA size relative to wild type mice (wild type 100.1% versus IL-6KO 76.5%, p = 0.04). The IL-6KO mice did not show protection from AAA (p = 0.732). Pharmacologic inhibition of IL-6 resulted in significant reduction in TAA size (tocilizumab 71.5% ± 13.2% versus vehicle 103.6% ± 20.7%, p = 0.005). Human TAA showed significantly greater IL-6 (p < 0.0001) compared with AAA and normal thoracic and abdominal aorta. CONCLUSIONS: Interleukin-6 is significantly greater in both murine and human TAA compared with AAA, suggesting fundamental differences in these disease processes. Interleukin-6 receptor antagonism attenuates experimental TAA formation, indicating that IL-6 may be a potential target for human thoracic aneurysmal disease.

Study of medical students' malpractice fear and defensive medicine: a "hidden curriculum?".

INTRODUCTION: Defensive medicine is a medical practice in which health care providers' primary intent is to avoid criticism and lawsuits, rather than providing for patients' medical needs. The purpose of this study was to characterize medical students' exposure to defensive medicine during medical school rotations. METHODS: We performed a cross-sectional survey study of medical students at the beginning of their third year. We gave students Likert scale questionnaires, and their responses were tabulated as a percent with 95% confidence interval (CI). RESULTS: Of the 124 eligible third-year students, 102 (82%) responded. Most stated they rarely worried about being sued (85.3% [95% CI=77.1% to 90.9%]). A majority felt that faculty were concerned about malpractice (55.9% [95% CI=46.2% to 65.1%]), and a smaller percentage stated that faculty taught defensive medicine (32.4% [95% CI=24.1% to 41.9%]). Many students believed their satisfaction would be decreased by MC and lawsuits (51.0% [95% CI=41.4% to 60.5%]). Some believed their choice of medical specialty would be influenced by MC (21.6% [95% CI=14.7% to 30.5%]), and a modest number felt their enjoyment of learning medicine was lessened by MC (23.5% [95% CI=16.4% to 32.6%]). Finally, a minority of students worried about practicing and learning procedures because of MC (16.7% [95% CI=10.7% to 25.1%]). CONCLUSION: Although third-year medical students have little concern about being sued, they are exposed to malpractice concerns and taught considerable defensive medicine from faculty. Most students believe that fear of lawsuits will decrease their future enjoyment of medicine. However, less than a quarter of students felt their specialty choice would be influenced by malpractice worries and that malpractice concerns lessened their enjoyment of learning medicine. [West J Emerg Med. 2014;15(3):293-298.].

Chest pain from excluded inferior vena cava filter after stent placement.

A 52-year-old patient presented with chronic substernal chest pain 18 months following exclusion of an inferior vena cava (IVC) filter with a self-expanding IVC stent. After a thorough work-up revealed no other possible cause of chest pain, the filter and stent were removed with subsequent resolution of chest pain. Intraoperatively, filter struts were found to have penetrated the posteromedial wall of the IVC and were abutting the periaortic neural plexus. Referred chest pain due to strut penetration of the caval wall is a novel complication of both IVC filters and IVC stents, demonstrating a need for continued surveillance.