These data suggest CFE should remain the standard of care for occlusive disease of the CFA. Its safety and efficacy establish a standard for comparison with emerging endovascular therapies.

Objectives Women have been shown to have up to a four-fold higher risk of abdominal aortic aneurysm (AAA) rupture at any given aneurysm diameter compared to men, leading to recommendations to offer repair to women at lower diameter thresholds. Although this higher risk of rupture may simply reflect greater relative aortic dilatation in women who have smaller aortas to begin with, this has never been quantified. Our objective was therefore to quantify the relationship between rupture and aneurysm diameter relative to body size and to determine whether a differential association between aneurysm diameter, body size, and rupture risk exists for men and women. Methods We performed a retrospective review of all patients in the Vascular Study Group of New England (VSGNE) database who underwent endovascular or open AAA repair. Using each patient’s height and weight, body mass index (BMI) and body surface area (BSA) were calculated. Next, indices of each measure of body size (height, weight, BMI, BSA) relative to aneurysm diameter were calculated for each patient. To generate these indices, we divided aneurysm diameter (in cm) by the measure of body size [e.g. aortic size index (ASI) = aneurysm diameter (cm) / BSA (m2)]. Along with other relevant clinical variables, we used these indices to construct different age-adjusted and multivariable-adjusted logistic regression models to determine predictors of ruptured repair vs. elective repair. Models for men and women were developed separately and different models were compared using the area under the curve (AUC). Results We identified 4045 patients who underwent AAA repair (78% male, 53% EVAR). Women had significantly smaller diameter aneurysms, lower BSA, and higher BSA indices than men (Table 1). For men, the variable that increased the odds of rupture the most was aneurysm diameter (AUC = 0.82). Men exhibited an increased rupture risk with increasing aneurysm diameter (<5.5cm: OR 1.0; 5.5–6.4cm: OR 0.9, 95% CI 0.5–1.7, P=.771; 6.5–7.4cm: OR 3.9, 95% CI 1.9–1.0, P<.001; 7.5+ cm: OR 11.3, 95% CI 4.9–25.8, P<.001). In contrast, the variable most predictive of rupture in women was ASI (AUC = 0.81), with higher odds of rupture at higher ASI(ASI >3.5–3.9: OR 6.4, 95% CI 1.7–24.1, P=.006; ASI 4.0+: OR 9.5, 95% CI 2.3–39.4, P=.002). For women, aneurysm diameter was not a significant predictor of rupture after adjusting for ASI. Conclusion Aneurysm diameter indexed to body size is the most important determinant of rupture for women whereas aneurysm diameter alone is most predictive of rupture for men. Women with the largest diameter aneurysms and the smallest body sizes are at the greatest risk of rupture.

A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)-mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor-B (NF-B). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell-mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders. IntroductionA20 is a zinc finger protein originally identified as a tumor necrosis factor (TNF)-responsive gene in endothelial cells (ECs). 1 A20 is expressed in multiple cell types in response to a variety of stimuli that activate the transcription factor nuclear factor-B (NF-B), including interleukin 1 (IL-1), lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), H 2 O 2 , and CD40 ligand. [2][3][4][5][6][7] We and others have demonstrated that A20, initially described as an antiapoptotic gene, is also a potent inhibitor of the transcription factor NF-B. 7-9 A20-null mice fail to terminate TNF-induced NF-B activation, develop severe inflammation and cachexia, and die prematurely, indicating the importance of A20 in the hierarchy of anti-inflammatory defense processes. 6,10 Elucidating the molecular basis and binding partner(s) that determine the inhibitory effect of A20 upon NF-B activation is the focus of ongoing research. 8 A20 has been shown to interact with components of the NF-B signaling cascade upstream of inhibitor of NF-B (IB), including TNF receptor-associated factors (TRAFs) 11,12 TRAF-1, TRAF-2, and TRAF-6; A20 binding inhibitors of NF-B; and the signalosome IB kinase-␥ (IKK␥)/NF-B essential modulator (NEMO) unit. [13][14][15] Further work is required to test the relevance of these interactions in blocking NF-B activation in response to stimuli other than TNF. 16 In contrast to its so far universal inhibitory effect on NF-B activation, the antiapoptotic activity of A20 remains controversial and appears to be specific to cell type and stimulus. Overexpression of A20 protects human breast carcinoma MCF-7 cells, murine fibrosarcoma WEHI 164, and murine embryonic NIH3T3, but not Hela and lung epithelial A459 cells from TNF-mediated apoptosis. 9,[17][18][19] In cultures derived from prima...

Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-␣, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinasedependent signaling pathways. PDGF-BB, tumor necrosis factor-␣, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27 kip1 , and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27 kip1 . In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27 kip1 in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.

The majority of patients with acute type B dissection will fail medical therapy over time as evidenced by a 6-year intervention-free survival of 41%. Patients who underwent any aortic intervention had a significant survival advantage over those who were treated with medical management alone. Further study is necessary to determine who will benefit most from early intervention.

There has been a significant increase in the use of TEVAR for management of diseases of the DTA. TEVAR offers a significant perioperative survival advantage when compared with OPEN regardless of the indication for repair. However, in the Medicare population, the 5-year survival is similar between the 2 cohorts.

Although primary patency is low, excellent limb salvage rates can be achieved in patients with CLI through close follow-up and secondary interventions. These data, and the 12% annual death rate, validate PTA as first-line therapy in patients with CLI.

Transplantation of an excessive number of islets of Langerhans (two to four pancreata per recipient) into patients with type I diabetes is required to restore euglycemia. Hypoxia, nutrient deprivation, local inflammation, and the β cell inflammatory response (up-regulation of NF-κB-dependent genes such as inos) result in β cell destruction in the early post-transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent β cell loss and primary nonfunction. We have shown in vitro that A20 inhibits NF-κB activation in islets and protects from cytokine- and death receptor-mediated apoptosis. In vivo, protection of newly transplanted islets would reduce the number of islets required for successful transplantation. Transplantation of 500 B6/AF1 mouse islets into syngeneic, diabetic recipients resulted in a cure rate of 100% within 5 days. Transplantation of 250 islets resulted in a cure rate of only 20%. Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets. A20-expressing islets preserve functional β cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.