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.

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.

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.

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.

Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo.

Laminar shear stress (SS) induces an antiproliferative and anti-inflammatory endothelial phenotype and increases Klf2 expression. We altered the diameter of an arteriovenous fistula (AVF) in the mouse model to determine whether increased fistula diameter produces disturbed SS in vivo and if acutely increased disturbed SS results in decreased Klf2 expression. The mouse aortocaval fistula model was performed with 22, 25, or 28 gauge needles to puncture the aorta and the inferior vena cava. Duplex ultrasound was used to examine the AVF and its arterial inflow and venous outflow, and SS was calculated. Arterial samples were examined with western blot, immunohistochemistry, and immunofluorescence analysis for proteins and qPCR for RNA. Mice with larger diameter fistulae had diminished survival but increased AVF patency. Increased SS magnitudes and range of frequencies were directly proportional to the needle diameter in the arterial limb proximal to the fistula but not in the venous limb distal to the fistula, with 22-gauge needles producing the most disturbed SS in vivo. Klf2 mRNA and protein expression was diminished in the artery proximal to the fistula in proportion to increasing SS. Increased fistula diameter produces increased SS magnitude and frequency, consistent with disturbed SS in vivo. Disturbed SS is associated with decreased mRNA and protein expression of Klf2. Disturbed SS and reduced Klf2 expression near the fistula are potential therapeutic targets to improve AVF maturation.

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.

Chronic kidney disease predicts long-term mortality after major lower extremity amputation.

BACKGROUND: Despite low peri-operative mortality after major lower extremity amputation, long-term mortality remains substantial. Metabolic syndrome is increasing in incidence and prevalence at an alarming rate in the USA. AIM: This study was to determine whether metabolic syndrome predicts outcome after major lower extremity amputation. PATIENTS AND METHODS: A retrospective review of charts between July 2005 and June 2010. RESULTS: Fifty-four patients underwent a total of 60 major lower extremity amputations. Sixty percent underwent below-knee amputation and 40% underwent above-knee amputation. The 30-day mortality was 7% with no difference in level (below-knee amputation, 8%; above-knee amputation, 4%; P = 0.53). The mean follow-up time was 39.7 months. The 5-year survival was 54% in the whole group, and was independent of level of amputation (P = 0.24) or urgency of the procedure (P = 0.51). Survival was significantly decreased by the presence of underlying chronic kidney disease (P = 0.04) but not by other comorbidities (history of myocardial infarction, P = 0.79; metabolic syndrome, P = 0.64; diabetes mellitus, P = 0.56). CONCLUSION: Metabolic syndrome is not associated with increased risk of adverse outcomes after lower extremity amputation. However, patients with chronic kidney disease constitute a sub-group of patients at higher risk of postoperative long-term mortality and may be a group to target for intervention.

Metabolic syndrome predicts restenosis after carotid endarterectomy.

BACKGROUND: Carotid endarterectomy (CEA) is an effective surgical option for stroke prophylaxis for most patients. Restenosis after CEA can lead to additional interventions and adverse outcomes, but the factors that predict restenosis are poorly understood. This study examined which risk factors, such as metabolic syndrome (MetS), are associated with restenosis after CEA. STUDY DESIGN: This retrospective study examined the records of all patients who underwent CEA at the Veterans Affairs Connecticut Healthcare System during a 4-year period. Metabolic syndrome was defined as the presence of 3 or more of the following: hypertension (blood pressure ≥130 mmHg/≥85 mmHg); serum triglycerides ≥150 mg/dL; high-density lipoprotein ≤40 mg/dL; BMI ≥25 kg/m(2); and fasting blood glucose ≥110 mg/dL. Major adverse events were defined as death, stroke, or MI. Restenosis was defined as >50% stenosis on follow-up imaging. RESULTS: Seventy-eight patients underwent 79 CEAs during the study period. All patients were male and 76% were white. Mean patient age was 72.6 years. The mean duration of follow-up was 5.2 years. Sixty-seven percent of patients had MetS. Patients with MetS were comparable with those without MetS in demographics and preoperative comorbidities, except for increased hypertension and diabetes, as expected, and chronic renal insufficiency (p = 0.05). There was no significant difference in long-term survival or freedom from MAE between patients with and without MetS. Restenosis was significantly higher in patients with MetS (p = 0.02) and occurred 2 years after CEA in patients with MetS only, with a large increase in restenosis after 5 years (p = 0.018). MetS was an independent predictor of restenosis in multivariable analysis (p = 0.01). CONCLUSIONS: Metabolic syndrome is an independent predictor for restenosis after CEA in a high-risk population. More frequent and/or long-term surveillance might be warranted in patients with MetS after CEA.

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.

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.

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.

Cell-based interventions for therapeutic angiogenesis: review of potential cell sources.

Alternative therapies are currently being developed to treat patients with chronic limb ischemia who are unable to be revascularized in order to avoid amputation. Cell-based therapy using mononuclear cells is gaining attention as many clinical trials are currently underway. We review cell differentiation along with the different potential cell sources for use in therapeutic angiogenesis.

Stem cell therapy for critical limb ischemia: what can we learn from cell therapy for chronic wounds?

Although much progress has been made regarding our knowledge of stem cells and their potential applications for therapeutic angiogenesis, there has been less success with the clinical application of this knowledge to patients with critical limb ischemia (CLI). Patients with CLI often have chronic wounds and newer cell-based therapies for chronic wounds show interesting parallels to stem cell therapy for CLI. Several human-derived wound care products and therapies, including human neonatal fibroblast-derived dermis (Dermagraft®), bilayered bioengineered skin substitute (Apligraf®), recombinant human platelet-derived growth factor and autologous platelet-rich plasma may provide insight into the mechanisms through which differentiated cells can be used as therapy for chronic wounds, and, analogously, by which stem cells might function therapeutically in CLI.

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.