Midterm outcomes of subclavian artery revascularization in the setting of thoracic endovascular aortic repair.

OBJECTIVE: The outcomes of subclavian artery revascularization (SAR) have been examined extensively in the setting of atherosclerotic occlusive disease but have been poorly characterized in the setting of thoracic endovascular aortic repair (TEVAR). As trials for branched thoracic endovascular stent grafts materialize, the outcomes of the subclavian artery branched prosthesis will need to be compared with TEVAR with SAR by carotid-subclavian bypass or subclavian transposition. METHODS: A database of 1516 patients undergoing TEVAR from 2000 to 2015 was queried. Of those undergoing TEVAR, 19% (282 patients) also underwent SAR. Patient demographics, TEVAR indication, 30-day morbidity and mortality, and midterm patency and survival were analyzed. RESULTS: During the study period, 282 patients underwent 288 SARs in the setting of TEVAR. A total of 269 (93%) carotid-subclavian bypasses and 19 (7%) subclavian artery transpositions were performed; 76% of the SARs occurred before TEVAR, 14% occurred concurrently with TEVAR, and 10% occurred after TEVAR. The most common indications for TEVAR was aortic aneurysm (56%), chronic aortic dissection with aneurysmal degeneration (23%), and aortic dissections (13%). The 30-day ipsilateral stroke rate was 3.5%. Eight patients (2.8%) underwent an unplanned return to the operating room (2.1% for hematoma evacuation and 0.7% for management of chyle leak). Six patients (2.1%) sustained a nerve injury. The mean follow-up was 4.2 years. All-cause 30-day mortality was 4.6%. The overall survival rates at 1 year, 5 years, and 10 years were 82%, 60%, and 42%, respectively. The median survival was 7.2 years. Four patients were found to have a failure in primary patency during follow-up. All four patients had undergone a carotid-subclavian bypass. The 1-, 2-, and 5-year primary patency rates were 99.5%, 98.9%, and 98.0%, respectively, for carotid-subclavian bypass and 100% for carotid-subclavian transposition. CONCLUSIONS: During our 16-year study, we found SAR in the setting of TEVAR to be associated with low morbidity, durable long-term patency, and infrequent need for reintervention.

Venous Mechanical Properties After Arteriovenous Fistulae in Mice.

BACKGROUND: An arteriovenous fistula (AVF) exposes the outflow vein to arterial magnitudes and frequencies of blood pressure and flow, triggering molecular pathways that result in venous remodeling and AVF maturation. It is unknown, however, how venous remodeling, that is lumen dilation and wall thickening, affects venous mechanical properties. We hypothesized that a fistula is more compliant compared with a vein because of altered contributions of collagen and elastin to the mechanical properties. METHODS: Ephb4+/- and littermate wild-type (WT) male mice were treated with sham surgery or needle puncture to create an abdominal aortocaval fistulae. The thoracic inferior vena cava was harvested 3 wk postoperatively for mechanical testing and histological analyses of collagen and elastin. RESULTS: Mechanical testing of the thoracic inferior vena cava from Ephb4+/- and WT mice showed increased distensibility and increased compliance of downstream veins after AVF compared with sham. Although Ephb4+/- veins were thicker than WT veins at the baseline, after AVF, both Ephb4+/- and WT veins showed similar wall thickness as well as similar collagen and elastin area fractions, but increased collagen undulation compared with sham. CONCLUSIONS: Fistula-induced remodeling of the outflow vein results in circumferentially increased distensibility and compliance, likely due to post-translational modifications to collagen.

Endovascular interventions decrease length of hospitalization and are cost-effective in acute mesenteric ischemia.

OBJECTIVE: Acute mesenteric ischemia (AMI) continues to be one of the most devastating diagnoses requiring emergent vascular intervention. There is a national trend toward increased use of endovascular procedures, with improved survival for the treatment of these patients. Our aim was to evaluate whether this trend has changed the treatment of AMI and the subsequent impact on length of hospitalization and hospitalization costs. METHODS: We identified all patients admitted for AMI from the National Inpatient Sample from 2004 to 2014 who received open surgical revascularization (OPEN) or an endovascular intervention (ENDO). Primary end points included length of hospital stay and cost of hospitalization. Our secondary end points included acute kidney injury (AKI), in-hospital mortality, and routine discharge. RESULTS: Among 10,381 discharges identified in the data set, 3833 (37%; 97.5% confidence interval [CI], 35%-39%) were male patients with a mean age of 69 years (range, 18-98 years); 4543 (44%; 97.5% CI, 41%-47%) patients were treated ENDO, and 5839 (56%; 97.5% CI, 53%-59%) patients were treated OPEN. Although a higher proportion of patients in the ENDO group (28%; 97.5% CI, 24%-31%) vs the OPEN group (14%; 97.5% CI, 11%-16%) had a moderate to severe Charlson Comorbidity Index (P < .0001), ENDO was associated with a lower mortality rate (12.3% [97.5% CI, 9.8%-14.8%] vs 33.1% [97.5% CI, 29.9%-36.2%]; P < .0001) and a lower mean hospitalization cost ($41,615 [97.5% CI, $38,663-$44,567] vs $60,286 [97.5% CI, $56,736-$63,836]; P < .0001). After propensity-adjusted logistic regression analysis, OPEN retained a significant association with higher mortality than ENDO (odds ratio, 3.0; 97.5% CI, 2.2-4.1) and with higher costs (mean, $9196; 97.5% CI, $3797-$14,595). Patients in the OPEN group had higher risk for AKI (P < .0001) and discharge to a skilled nursing facility (P < .0001) rather than home. CONCLUSIONS: Although the rate of ENDO continues to rise nationally, it still has not surpassed OPEN revascularization in the face of AMI. Patients treated endovascularly demonstrated one-third the rate of in-hospital mortality (odds ratio, 3.0; 97.5% CI, 2.2-4.1), an increased hazard ratio for discharge alive (hazard ratio, 2.27; 97.5% CI, 2.00-2.58), and a cost saving of $9196 (97.5% CI, $3797-$14,595) per hospitalization. Furthermore, they were less likely to develop AKI and to be discharged home after hospitalization.

Improved mortality in treatment of patients with endovascular interventions for chronic mesenteric ischemia.

OBJECTIVE: Chronic mesenteric ischemia (CMI) continues to be a devastating diagnosis. There is a national trend toward increased use of endovascular procedures with improved survival for the treatment of these patients. Our aim was to evaluate whether this trend has changed CMI patients' length of hospitalization and health care cost. METHODS: We identified all patients admitted for CMI from the National Inpatient Sample (NIS) from 2000 to 2014. Our primary end points included length of hospital stay (LOS) and cost of hospitalization (COH). Our secondary end points included mortality assessment of the CMI hospitalization. RESULTS: There were 15,475 patients admitted for CMI. The mean age of patients was 71 years, and 4022 (26.0%) were male. There were 10,920 (70.6%) patients treated endovascularly (ENDO) and 4555 (29.4%) patients treated in an open fashion (OPEN). Although a higher proportion of patients in the ENDO (43.3%) group vs OPEN (33.1%) had a Charlson Comorbidity Index score of ≥2 (P < .0001), they had a lower mortality rate (2.4% vs 8.7%; P < .0001), lower mean LOS (6.3 vs 14.0 days; P < .0001), and lower COH ($21,686 vs $42,974; P < .0001). After adjusting for clinical and hospital factors, OPEN continued to demonstrate higher mortality than ENDO (odds ratio, 7.2; 95% confidence interval, 4.9-10.6; P < .0001), longer LOS (mean, +9.7 days; P < .0001), and higher COH (mean, +$25,834; P < .0001). CONCLUSIONS: The rate of ENDO continues to rise nationally in the treatment of CMI patients. After adjusting for clinical and hospital factors, patients in the ENDO group tend to have lower in-hospital mortality of 2.4% and lower LOS by 10 days, and they incur a cost saving of >$25,000 compared with patients in the OPEN group. ENDO should be considered first line of therapy for patients with CMI.

CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation.

OBJECTIVE: Arteriovenous fistulae (AVF) remain the optimal conduit for hemodialysis access but continue to demonstrate poor patency and poor rates of maturation. We hypothesized that CD44, a widely expressed cellular adhesion molecule that serves as a major receptor for extracellular matrix components, promotes wall thickening and extracellular matrix deposition during AVF maturation. APPROACH AND RESULTS: AVF were created via needle puncture in wild-type C57BL/6J and CD44 knockout mice. CD44 mRNA and protein expression was increased in wild-type AVF. CD44 knockout mice showed no increase in AVF wall thickness (8.9 versus 26.8 µm; P=0.0114), collagen density, and hyaluronic acid density, but similar elastin density when compared with control AVF. CD44 knockout mice also showed no increase in vascular cell adhesion molecule-1 expression, intercellular adhesion molecule-1 expression, and monocyte chemoattractant protein-1 expression in the AVF compared with controls; there were also no increased M2 macrophage markers (transglutaminase-2: 81.5-fold, P=0.0015; interleukin-10: 7.6-fold, P=0.0450) in CD44 knockout mice. Delivery of monocyte chemoattractant protein-1 to CD44 knockout mice rescued the phenotype with thicker AVF walls (27.2 versus 14.7 µm; P=0.0306), increased collagen density (2.4-fold; P=0.0432), and increased number of M2 macrophages (2.1-fold; P=0.0335). CONCLUSIONS: CD44 promotes accumulation of M2 macrophages, extracellular matrix deposition, and wall thickening during AVF maturation. These data show the association of M2 macrophages with wall thickening during AVF maturation and suggest that enhancing CD44 activity may be a strategy to increase AVF maturation.

Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation.

BACKGROUND: The poor clinical results that are frequently reported for arteriovenous fistulae (AVF) for hemodialysis are typically due to failure of AVF maturation. We hypothesized that early AVF maturation is associated with generation of reactive oxygen species and activation of the hypoxia-inducible factor-1 (HIF-1) pathway, potentially promoting neointimal hyperplasia. We tested this hypothesis using a previously reported mouse AVF model that recapitulates human AVF maturation. METHODS: Aortocaval fistulae were created in C57Bl/6 mice and compared with sham-operated mice. AVFs or inferior vena cavas were analyzed using a microarray, Amplex Red for extracellular H2O2, quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting for HIF-1α and immunofluorescence for NOX-2, nitrotyrosine, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF)-A. RESULTS: Oxidative stress was higher in AVF than that in control veins, with more H2O2 (P = 0.007) and enhanced nitrotyrosine immunostaining (P = 0.005). Immunohistochemistry and immunoblot showed increased HIF-1α immunoreactivity in the AVF endothelium; HIF-1 targets NOX-2, HO-1 and VEGF-A were overexpressed in the AVF (P < 0.01). AVF expressed increased numbers of HIF-1α (P < 0.0001) and HO-1 (P < 0.0001) messenger RNA transcripts. CONCLUSIONS: Oxidative stress increases in mouse AVF during early maturation, with increased expression of HIF-1α and its target genes NOX-2, HO-1, and VEGF-A. These results suggest that clinical strategies to improve AVF maturation could target the HIF-1 pathway.

Ephrin type-B receptor 4 activation reduces neointimal hyperplasia in human saphenous vein in vitro.

BACKGROUND: Vein bypass is an essential therapy for patients with advanced peripheral and coronary artery disease despite development of neointimal hyperplasia. We have shown that stimulation of the receptor tyrosine kinase ephrin type-B receptor 4 (Eph-B4) with its ligand ephrin-B2 prevents neointimal hyperplasia in murine vein grafts. This study determines whether Eph-B4 in adult human veins is capable of phosphorylation and activation of downstream signaling pathways, as well as functional to release nitric oxide (NO) and prevent neointimal hyperplasia in vitro. METHODS: Discarded human saphenous veins were taken from the operating room and placed in organ culture without or with ephrin-B2/Fc (2 µg/mL) for 14 days, and the neointima/media ratio was measured in matched veins. Primary human umbilical vein endothelial cells were treated with ephrin-B2/Fc (2 µg/mL) and examined with quantitative polymerase chain reaction, Western blot, immunoassays, and for release of NO. Ephrin-B2/Fc (2 µg/mL) was placed on the adventitia of saphenous veins treated with arterial shear stress for 24 hours in a bioreactor and activated Eph-B4 examined with immunofluorescence. RESULTS: The baseline intima/media ratio in saphenous vein rings was 0.456 ± 0.097, which increased to 0.726 ± 0.142 in untreated veins after 14 days in organ culture but only to 0.630 ± 0.132 in veins treated with ephrin-B2/Fc (n = 19, P = .017). Ephrin-B2/Fc stimulated Akt, endothelial NO synthase and caveolin-1 phosphorylation, and NO release (P = .007) from human umbilical vein endothelial cells (n = 6). Ephrin-B2/Fc delivered to the adventitia stimulated endothelial Eph-B4 phosphorylation after 24 hours of arterial stress in a bioreactor (n = 3). CONCLUSIONS: Eph-B4 is present and functional in adult human saphenous veins, with intact downstream signaling pathways capable of NO release and prevention of neointimal hyperplasia in vitro. Adventitial delivery of ephrin-B2/Fc activates endothelial Eph-B4 in saphenous veins treated with arterial shear stress in vitro. These results suggest that stimulation of Eph-B4 function may be a candidate strategy for translation to human clinical trials designed to inhibit venous neointimal hyperplasia.

Metabolic syndrome is associated with type II endoleak after endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Type II endoleak is usually a benign finding after endovascular abdominal aortic aneurysm repair (EVAR). In some patients, however, type II endoleak leads to aneurysm sac expansion and the need for further intervention. We examined which factors, in particular the components of metabolic syndrome (MetS), would lead to an increase risk of endoleak after EVAR. METHODS: The medical records of all patients who underwent EVAR between 2002 and 2011 at the Veterans Affairs Connecticut Healthcare System were reviewed. MetS was defined as the presence of three or more of the following: hypertension (blood pressure ≥130 mm Hg/≥90 mm Hg), serum triglycerides ≥150 mg/dL, serum high-density lipoproteins ≤50 mg/dL for women and ≤40 mg/dL for men, body mass index ≥30 kg/m(2), and fasting blood glucose ≥110 mg/dL. Development of endoleak, including specific endoleak type, was determined by review of standard radiologic surveillance. RESULTS: During a 9-year period, 79 male patients (mean age, 73.5 years), underwent EVAR for infrarenal abdominal aortic aneurysm (mean 6.2 cm maximal transverse diameter). MetS was present in 52 patients (66%). The distribution of MetS factors among all patients was hypertension in 86%, hypertriglyceridemia in 72%, decreased high-density lipoprotein in 68%, diabetes in 37%, and a body mass index of ≥30 kg/m(2) in 30%. No survival difference was found between the MetS and non-MetS groups (P = .66). There was no difference in perioperative myocardial infarction or visceral ischemia immediately postoperatively between the two groups. Patients with MetS had a significant increase in acute kidney injury (n = 7, P = .0128). Endoleaks of all types were detected in 26% (n = 20) of all patients; patients with MetS had more endoleaks than patients without MetS (35% vs 7.4%, P = .0039). Of the 19 type II endoleaks, 79% were present at the time of EVAR and only 21% developed during surveillance; 95% had MetS (P = .0007). CONCLUSIONS: Type II endoleak after EVAR for abdominal aortic aneurysm is associated with MetS. Whether these patients are subject to more subsequent intervention due to sac expansion is unclear. MetS may be a factor to consider in the treatment of type II endoleak.

Vein graft adaptation and fistula maturation in the arterial environment.

Veins are exposed to the arterial environment during two common surgical procedures, creation of vein grafts and arteriovenous fistulae (AVF). In both cases, veins adapt to the arterial environment that is characterized by different hemodynamic conditions and increased oxygen tension compared with the venous environment. Successful venous adaptation to the arterial environment is critical for long-term success of the vein graft or AVF and, in both cases, is generally characterized by venous dilation and wall thickening. However, AVF are exposed to a high flow, high shear stress, low-pressure arterial environment and adapt mainly via outward dilation with less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high-pressure arterial environment and adapt mainly via increased wall thickening with less outward dilation. We review the data that describe these differences, as well as the underlying molecular mechanisms that mediate these processes. Despite extensive research, there are few differences in the molecular pathways that regulate cell proliferation and migration or matrix synthesis, secretion, or degradation currently identified between vein graft adaptation and AVF maturation that account for the different types of venous adaptation to arterial environments.

Heterogeneous gene expression during early arteriovenous fistula remodeling suggests that downregulation of metabolism predicts adaptive venous remodeling.

Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a 'normal' AVF (nAVF) group and an 'outliers' (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.

The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation.

Several models of arteriovenous fistula (AVF) have excellent patency and help in understanding the mechanisms of venous adaptation to the arterial environment. However, these models fail to exhibit either maturation failure or fail to develop stenoses, both of which are critical modes of AVF failure in human patients. We used high-resolution Doppler ultrasound to serially follow mice with AVFs created by direct 25-gauge needle puncture. By day 21, 75% of AVFs dilate, thicken, and increase flow, i.e., mature, and 25% fail due to immediate thrombosis or maturation failure. Mature AVF thicken due to increased amounts of smooth muscle cells. By day 42, 67% of mature AVFs remain patent, but 33% of AVFs fail due to perianastomotic thickening. These results show that the mouse aortocaval model has an easily detectable maturation phase in the first 21 days followed by a potential failure phase in the subsequent 21 days. This model is the first animal model of AVF to show a course that recapitulates aspects of human AVF maturation.

The influence of metabolic syndrome on hemodialysis access patency.

OBJECTIVE: The natural history of patients with metabolic syndrome (MetS) undergoing hemodialysis access placement is unknown. MetS has previously been found as a risk factor for poor outcomes for vascular surgery patients undergoing other interventions. The aim of this is study is to describe the outcomes of MetS patients undergoing primary hemodialysis access placement. METHODS: The medical records of the 187 patients who underwent hemodialysis access placement between 1999 and 2009 at the Veterans Administration Connecticut Healthcare System were reviewed. Survival, primary patency, and secondary patency were evaluated using the Gehan-Breslow test for survival. MetS was defined as the presence of three or more of the following: blood pressure≥130/90 mm Hg; triglycerides≥150 mg/dL; high-density lipoprotein≤50 mg/dL for women and ≤40 mg/dL for men; body mass index≥30 kg/m2; or fasting blood glucose≥110 mg/dL. RESULTS: Of the 187 patients who underwent hemodialysis access placement, 115 (61%) were identified to have MetS. The distribution of MetS factors among all patients was hypertension in 98%, diabetes in 58%, elevated triclyceride in 39%, decreased high-density lipoprotein in 60%, elevated body mass index in 36%, and 39% were currently receiving hemodialysis. Patients were a mean age of 66 years. The median length of follow-up was 4.2 years. The forearm was site of fistula placement in 53%; no difference existed between groups (MetS, 57%; no MetS, 50%; P=.388). The median time to primary failure was 0.46 years for all patients (MetS, 0.555 years; no MetS, 0.436 years; P=.255). Secondary patency was 50% at 1.18 years for all patients (no MetS, 1.94 years; MetS, 0.72 years; P=.024). Median survival duration for all patients was 4.15 years (no MetS, 5.07 years; MetS, 3.63 years; P=.019). CONCLUSIONS: MetS is prevalent among patients undergoing hemodialysis access placement. Patients with MetS have equivalent primary patency rates; however, their survival and cumulative patency rates are significantly lower than in patients without MetS. Patients with MetS form a high-risk group that needs intensive surveillance protocols.

Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis.

INTRODUCTION: Several clinical trials are currently evaluating stem cell therapy for patients with critical limb ischemia that have no other surgical or endovascular options for revascularization. However, these trials are conducted with different protocols, including use of different stem cell populations and different injection protocols, providing little means to compare trials and guide therapy. Accordingly, we developed a murine model of severe ischemia to allow methodic testing of relevant clinical parameters. METHODS: High femoral artery ligation and total excision of the superficial femoral artery was performed on C57BL/6 mice. Mononuclear cells (MNCs) were isolated from the bone marrow of donor mice, characterized using fluorescence-activated cell sorting, and injected (5×10(5) to 2×10(6)) into the semimembranosus (proximal) or gastrocnemius (distal) muscle. Vascular and functional outcomes were measured using invasive Doppler imaging, laser Doppler perfusion imaging, and the Tarlov and ischemia scores. Histologic analysis included quantification of muscle fiber area and number as well as capillary density. RESULTS: Blood flow and functional outcomes were improved in MNC-treated mice compared with controls over 28 days (flow: P<.0001; Tarlov: P=.0004; ischemia score: P=.0002). MNC-treated mice also showed greater gastrocnemius fiber area (P=.0053) and increased capillary density (P=.0004). Dose-response analysis showed increased angiogenesis and gastrocnemius fiber area but no changes in macroscopic vascular flow or functional scores. Overall functional outcomes in mice injected proximally to the ischemic area were similar to mice injected more distally, but muscle flow, capillary density, and gastrocnemius fiber area were increased (P<.05). CONCLUSIONS: High femoral ligation with complete excision of the superficial femoral artery is a reliable model of severe hind limb ischemia in C57BL/6 mice that shows a response to MNC treatment for functional and vascular outcomes. A dose response to the injection of MNCs appears to be present, at least microscopically, suggesting that an optimal cell number for stem cell therapy exists and that preclinical testing needs to be performed to optimally guide human trials. Injection of MNCs proximal to the site of ischemia may provide different outcomes compared with distal injection and warrants additional study.

Renal artery interventions during infrarenal endovascular aortic repair: a greater potential of subsequent failure?

PURPOSE: To determine the anatomic and functional outcomes of renal artery interventions during endovascular aortic aneurysm repair (EVAR) and compare them with renal artery interventions without EVAR. MATERIALS AND METHODS: A renal artery revascularization database (1987-2007) was reviewed to identify patients who underwent renal intervention during EVAR and those who had an intervention in the absence of EVAR. Outcomes were analyzed with respect to patient comorbidities, renal anatomy and function, procedural events, and postoperative complications. RESULTS: A total of 413 patients (239 men; 58%) underwent 589 renal artery revascularizations (51 with EVAR and 362 without). Mean age was 70 years +/- 10. Mean follow-up was 3.5 years (range, 1-13 y). Primary indications for renal intervention were hypertension (63%) and elevated creatinine level (27%). The EVAR group was more likely to incur an increased creatinine level at 1 month after intervention (33% vs 18%; P = .007). Freedom from restenosis was similar (P = .501), but arterial occlusion rate was higher in the EVAR group (96% +/- 3% vs 100% +/- 10% cumulative patency at 3 y; P = .005). At 3 years, freedom from recurrent symptoms (P = .26), freedom from adverse renal events (P = .12), and survival (85% +/- 8% vs 75% +/- 2%; P = .83) were not significantly different. CONCLUSIONS: Renal artery revascularization during EVAR should be considered higher risk because of the high incidence of procedural complications, early functional injury, and early occlusion rates. However, the long-term sequelae and benefits of such a procedure are similar to those of a renal revascularization procedure in the absence of EVAR.

Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanism.

BACKGROUND: Cell migration is an integral component of intimal hyperplasia development and proteases are pivotal in the process. Understanding the role of urokinase signaling within the cells of vasculature remains poorly defined. The study examines the role of amino-terminal fragment (ATF) of urokinase on a pivotal cross-talk receptor, epidermal growth factor receptor (EGFR). EGFR is transactivated by both G-protein-coupled receptors and receptor tyrosine kinases and is key to many of their responses. We hypothesize that A Disintegrin and Metalloproteinase Domains (ADAM) allows the transactivation of EGFR by ATF. OBJECTIVE: To determine the role of ADAM in EGFR transactivation by ATF in human vascular smooth muscle cells (VSMC) during cell migration. METHODS: Human coronary VSMC were cultured in vitro. Assays of EGFR phosphorylation were examined in response to ATF (10 nM) in the presence and absence of the matrix metalloprotease (MMP) inhibitor GM6001, the ADAM inhibitors TAPI-0 and TAPI-1, heparin binding epidermal growth factor (HB-EGF) inhibitor, CRM197, HB-EGF inhibitory antibodies, epidermal growth factor (EGF) inhibitory antibodies, and the EGFR inhibitor AG1478. The small interference ribonucleic acid (siRNA) against EGFR and ADAM-9, ADAM-10, ADAM-12, and adenoviral delivered Gbg inhibitor, betaARK(CT) were also used. RESULTS: ATF produced concentration-dependent VSMC migration (by wound assay and Boyden chamber), which was inhibited by increasing concentrations of AG1478. ATF was shown to induce time-dependent EGFR phosphorylation, which peaked at fourfold greater than control. Pre-incubation with the Gbetagamma inhibitor betaARK(CT) inhibited EGFR activation by ATF. This migratory and EGFR response was inhibited by AG1478 in a concentration-dependent manner. Incubation with siRNA against EGFR blocked the ATF-mediated migratory and EGFR responses. EGFR phosphorylation by ATF was blocked by inhibition of MMP activity and the ligand HB-EGF. The presence of the ADAM inhibitors, TAPI-0 and TAPI-1 significantly decreased EGFR activation. EGFR phosphorylation by EGF was not interrupted by inhibition of MMP, ADAMs, or HB-EGF. Direct blockade of the EGFR prevented activation by both ATF and EGF. Incubation with siRNA to ADAM-9 and -10 significantly reduced HB-EGF release from VSMC and EGFR activation in response to ATF. The siRNA against ADAM-12 had no effect. CONCLUSION: ATF can induce transactivation of EGFR by an ADAM-mediated, HB-EGF-dependent process. Targeting a pivotal cross-talk receptor such as EGFR is an attractive molecular target to inhibit cell migration.

Metabolic syndrome: A predictor of adverse outcomes after carotid revascularization.

BACKGROUND: Metabolic syndrome (MetS) is rapidly increasing in prevalence and is associated with carotid plaque development and is a risk factor for stroke. The aim of this study is to describe the outcomes for patients with MetS after carotid revascularization (carotid endarterectomy [CEA] and carotid stenting [CAS]). METHODS: A database of patients undergoing carotid revascularization for primary atherosclerotic lesions was queried from 1996 to 2006. MetS was defined as the presence of >or=3 of the following criteria: blood pressure >or=130 mm Hg/>or=90 mm Hg; Triglycerides >or=150 mg/dL; high-density lipoproteins (HDL) or=110 mg/dL; or Body Mass Index (BMI) >or=30 kg/m(2). Multivariate and Kaplan-Meier analyses were performed to outcomes. The average follow-up period was 4.5 years. A major adverse event (MAE) was defined as the occurrence of stroke, myocardial infarction (MI), or death. RESULTS: A total of 921 patients (mean age: 71 +/- 10 years; 64% male) underwent 750 CEAs and 171 CAS. Thirty-one percent were identified as having MetS, 48% were asymptomatic, 87% had hypertension, 27% had hyperlipidemia, 32% were considered diabetic, and 14% had chronic renal insufficiency. The morbidity and mortality rates for all patients were 16.9% and 1.1%, respectively. The 30-day combined stroke/death rate was 3.6%. The 30-day MAE rates were: 6.7% vs 3.3% for MetS vs No-MetS (P = .02). The 90-day MAE rates were 8.7% vs 4.9% for MetS vs No-MetS (P = .03). MetS patients were more likely to experience a complication than No-MetS patients (23% vs 14%, P = .001). By Kaplan-Meier analysis, there was no difference between MetS and No-MetS patients with respect to patency, restenosis, re-intervention, or survival, but a difference existed for freedom from stroke, MI, and MAE. The difference between stroke rates was maintained between MetS and No-MetS, when subgrouped by those with and without symptoms. For patients with diabetes mellitus (DM), those with MetS had a 68% and 410% higher risk of developing an MAE and MI, respectively. However, for patients without diabetes, MetS was not significantly associated with MAE, stroke, or MI. No factors were found to be significantly associated with risk of stroke in all cases (in all patients, patients with diabetes, and patients without diabetes). CONCLUSION: MetS is prevalent among patients undergoing carotid revascularization. MetS patients are at a greater risk for perioperative morbidity as well as stroke, MI, and MAE during follow-up when compared to patients without MetS. Long-term stroke prevention is poor in the presence of MetS. MetS should be considered a significant risk factor for patients undergoing carotid revascularization.

Impact of chronic kidney disease on outcomes of superficial femoral artery endoluminal interventions.

While aggressive endoluminal therapy for superficial femoral artery (SFA) occlusive disease is commonplace, the implications of chronic kidney disease (CKD) on long-term outcomes in this population are unclear. We examined the consequences of endovascular treatment of the SFA in patients with and without varying stages of CKD. A database of patients undergoing endovascular treatment of the SFA between 1986 and 2007 was queried, and two groups were defined: estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 cm(2). Intention-to-treat analysis was performed. Results were standardized to TransAtlantic Inter-Society Consensus (TASC-II) and Society for Vascular Surgery criteria. Kaplan-Meier analyses were performed to assess time-dependent outcomes. Factor analyses were performed using a Cox proportional hazard model for time-dependent variables. Data are presented as mean +/- standard deviation where appropriate. There were 525 limbs in 535 patients (68% male, average age 66 +/- 14 years) that underwent endovascular treatment for claudication or chronic critical limb ischemia (51%). Patients with eGFR 60. In patients with critical limb ischemia, there was no difference in patency between those with eGFR 60. Limb salvage was worse in patients with eGFR 60. With respect to limb salvage, six factors were significantly associated with a reduction in rates: presence of tissue loss at presentation (relative risk [RR] = 6.45, p = 0.003), 0 or 1 vessel tibial runoff (RR = 2.56, p < 0.01), progression of distal disease noted in follow-up (RR = 4.62, p < 0.01), embolization at the initial intervention (RR = 2.70, p < 0.05), diabetes mellitus (RR = 3.71, p < 0.01), and a history of congestive heart disease (RR = 2.42, p < 0.01). Notable factors that were not significantly associated included lesion calcification (p = 0.64), TASC C or D lesion categorization (p = 0.99), acute occlusion at initial intervention (p = 0.40), and adjuvant stenting (p = 0.67). CKD does not impact the patency of SFA interventions. Limb salvage in patients with critical ischemia is significantly worse when the eGFR is

Hybrid debranching-endovascular repair of visceral patch aneurysm after thoracoabdominal aneurysm repair.

A visceral patch aneurysm is a significant complication after extensive thoracoabdominal aneurysm repair, and open procedures to correct these lesions are associated with a high perioperative mortality. We report the case of a 6-cm visceral patch aneurysm occurring in a patient with a completely replaced descending and abdominal aorta that was successfully corrected by staged debranching and endovascular repair with a dedicated thoracic endograft. Hybrid procedures are a successful option to treat complex repairs in the reoperative setting. They have the potential to lower perioperative risk and enhance patient care.

Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency.

Low rates of arteriovenous fistula (AVF) maturation prevent optimal fistula use for hemodialysis; however, the mechanism of venous remodeling in the fistula environment is not well understood. We hypothesized that the embryonic venous determinant Eph-B4 mediates AVF maturation. In human AVF and a mouse aortocaval fistula model, Eph-B4 protein expression increased in the fistula vein; expression of the arterial determinant Ephrin-B2 also increased. Stimulation of Eph-B-mediated signaling with Ephrin-B2/Fc showed improved fistula patency with less wall thickness. Mutagenesis studies showed that tyrosine-774 is critical for Eph-B4 signaling and administration of inactive Eph-B4-Y774F increased fistula wall thickness. Akt1 expression also increased in AVF; Akt1 knockout mice showed reduced fistula diameter and wall thickness. In Akt1 knockout mice, stimulation of Eph-B signaling with Ephrin-B2/Fc showed no effect on remodeling. These results show that AVF maturation is associated with acquisition of dual arteriovenous identity; increased Eph-B activity improves AVF patency. Inhibition of Akt1 function abolishes Eph-B-mediated venous remodeling suggesting that Eph-B4 regulates AVF venous adaptation through an Akt1-mediated mechanism.

Temporal regulation of venous extracellular matrix components during arteriovenous fistula maturation.

PURPOSE: The venous limb of arteriovenous fistulae (AVF) adapts to the arterial environment by dilation and wall thickening; however, the temporal regulation of the expression of extracellular matrix (ECM) components in the venous limb of the maturing AVF has not been well characterized. We used a murine model of AVF maturation that recapitulates human AVF maturation to determine the temporal pattern of expression of these ECM components. METHODS: Aortocaval fistulae were created in C57BL/6J mice and the venous limb was analyzed on postoperative days 1, 3, 7, 21, and 42. A gene microarray analysis was performed on day 7; results were confirmed by qPCR, histology, and immunohistochemistry. Proteases, protease inhibitors, collagens, glycoproteins, and other non-collagenous proteins were characterized. RESULTS: The maturing AVF has increased expression of many ECM components, including increased collagen and elastin. Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP1) showed increased mRNA and protein expression during the first 7 days of maturation. Increased collagen and elastin expression was also significant at day 7. Expression of structural proteins was increased later during AVF maturation. Osteopontin (OPN) expression was increased at day 1 and sustained during AVF maturation. CONCLUSIONS: During AVF maturation, there is significantly increased expression of ECM components, each of which shows distinct temporal patterns during AVF maturation. Increased expression of regulatory proteins such as MMP and TIMP precedes increased expression of structural proteins such as collagen and elastin, potentially mediating a controlled pattern of ECM degradation and vessel remodeling without structural failure.