Causes of severe chronic venous insufficiency.

A large number of adults in this country have some form of chronic venous insufficiency and a significant percentage of these have venous ulcers. The past decade has refined understanding of leukocyte-mediated injury and has elucidated the role of inflammatory processes in the dermal pathology of chronic venous insufficiency. Understanding of these pathologic cellular functions and molecular regulation of these processes is increasing.

Observer variability of iliac artery measurements in endovascular repair of abdominal aortic aneurysms.

Accurate measurement of iliac arteries is essential for successful delivery of aortic endografts without iliac limb endoleak. Although intravascular ultrasound measurements may be reliable, they require an invasive procedure. Therefore, helical computed tomography (hCT) has become the most commonly used modality for obtaining preprocedure arterial diameter measurements. The accuracy of hCT remains ill-defined, however, because an anatomic gold standard with which to compare the measurements is not available. We therefore assessed inter- and intraobserver variability of hCT measurements. We also applied accepted cutoff measurements to determine the clinical impact of observer variability in predicting the need for adjunctive iliac access and iliac limb seal procedures. hCT scans were analyzed in 30 patients who had undergone successful placement of a bifurcated endograft (26 Ancure, 4 Aneurex). Mean age of patients was 75 years, the male/female ratio was 27:3. Three blinded observers measured transverse diameters (maximal aortic aneurysm [Amax], narrowest infrarenal aortic neck [Amin], maximal common iliac [Imax], and narrowest iliac artery [Imin]). Inter- and intraobserver variability was calculated as standard deviation of mean pair differences according to the method of Bland and Altman. The true incidence of adjunctive procedures to facilitate delivery of the device into the aorta and ensure iliac limb seal was compared with that predicted by the observers to obtain sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for the measurements. Interobserver variability of iliac measurements was higher than intraobserver variability (p < 0.05). Interobserver variability of Amax ranged from 4.37 to 10.73% of the mean Amax. Conversely, variability of Amin was 8.91-18.89%, that of Imax was 12.11-22.23%, and that of Imin was 10.51-18.73% (p < 0.05 vs. Amax). Therefore, interobserver variability influenced aortic neck and iliac diameter twice as much as it did aneurysm measurements. To successfully place 30 endografts we performed 8 adjunctive access procedures (4 angioplasties, 4 common iliac artery conduits) and 17 adjunctive procedures in 60 limbs to ensure limb seal (9 unilateral IIA coil embolizations, 8 stents). We used 8.5 (Ancure) and 8.0 (Aneurex) mm as lower limits of acceptability for uncomplicated access, and 13.4 (Ancure) and 16 (Aneurex) mm as the upper limits of acceptability for uncomplicated iliac limb seal. These limits were applied to measurements from the three observers to predict need for adjunctive access or iliac seal procedures in this cohort. Sensitivity, specificity, PPV, and NPV of these observer measurements for a need to perform additional access procedures were 0.67, 0.80, 0.55, and 0.87; the same values for a need to perform additional seal procedures were 0.71, 0.74, 0.52, and 0.86, respectively. Interobserver variability was approximately 20% of measured iliac diameter. This explains why helical CT measurements were noted to have low PPV in predicting the need for an adjunctive access or limb seal procedure. These data establish PPV and NPV for hCT and provide objective evidence for the need to improve iliac artery imaging. Until more accurate imaging becomes available, we recommend oversizing of iliac limbs by 10-20% in patients with wide landing zones and that surgeons be prepared to resolve unexpected iliac artery access or seal problems intraoperatively.

In-stent recurrent stenosis after carotid artery stenting: life table analysis and clinical relevance.

OBJECTIVES: Carotid artery stenting has been proposed as an alternative to carotid endarterectomy in cerebral revascularization. Although early results from several centers have been encouraging, concerns remain regarding long-term durability of carotid artery stenting. We report the incidence, characteristics, and management of in-stent recurrent stenosis after long-term follow-up of carotid artery stenting. METHODS: Carotid artery stenting (n = 122) was performed in 118 patients between September 1996 and March 2003. Indications included recurrent stenosis after previous carotid endarterectomy (66%), primary lesions in patients at high-risk (29%), and previous ipsilateral cervical radiation therapy (5%). Fifty-five percent of patients had asymptomatic stenosis; 45% had symptomatic lesions. Each patient was followed up with serial duplex ultrasound scanning. Selective angiography and repeat intervention were performed when duplex ultrasound scans demonstrated 80% or greater in-stent recurrent stenosis. Data were prospectively recorded, and were statistically analyzed with the Kaplan-Meier method and log-rank test. RESULTS: Carotid artery stenting was performed successfully in all cases, with the WallStent or Acculink carotid stent. Thirty-day stroke and death rate was 3.3%, attributable to retinal infarction (n = 1), hemispheric stroke (n = 1), and death (n = 2). Over follow-up of 1 to 74 months (mean, 18.8 months), 22 patients had in-stent recurrent stenosis (40%-59%, n = 11; 60%-79%, n = 6; > or =80%, n = 5), which occurred within 18 months of carotid artery stenting in 13 patients (60%). None of the patients with in-stent recurrent stenosis exhibited neurologic symptoms. Life table analysis and Kaplan-Meier curves predicted cumulative in-stent recurrent stenosis 80% or greater in 6.4% of patients at 60 months. Three of five in-stent recurrent stenoses occurred within 15 months of carotid artery stenting, and one each occurred at 20 and 47 months, respectively. Repeat angioplasty was performed once in 3 patients and three times in 1 patient, and repeat stenting in 1 patient, without complications. One of these patients demonstrated asymptomatic internal carotid artery occlusion 1 year after repeat intervention. CONCLUSIONS: Carotid artery stenting can be performed with a low incidence of periprocedural complications. The cumulative incidence of clinically significant in-stent recurrent stenosis (> or =80%) over 5 years is low (6.4%). In-stent restenosis was not associated with neurologic symptoms in the 5 patients noted in this cohort. Most instances of in-stent recurrent stenosis occur early after carotid artery stenting, and can be managed successfully with endovascular techniques.

Durability and cumulative functional patency of transposed and nontransposed arteriovenous fistulas.

OBJECTIVES: Preoperative duplex scanning of arm and forearm veins has increased the creation of autogenous arteriovenous (AV) fistulas. However, the cumulative functional patency and durability of transposed AV fistulas (TAVF) compared with nontransposed AV fistulas (AVF) and prosthetic bridging grafts (AVG) remains ill-defined. METHODS: From January 1998 to December 2002, 245 dialysis access procedures were performed at University Hospital and the Veteran Affairs Medical Center in New Jersey. Follow-up data were available for 125 procedures (TAVF, n = 42; AVF, n = 30; AVG, n = 53) performed in 97 patients. All access procedures were planned on the basis of preoperative duplex scans of arm and forearm veins. Functional patency was defined as ability to cannulate and hemodialyze patients successfully. Primary and secondary cumulative functional patency of TAVFs, AVFs, and AVGs was determined with life table analysis, and differences were analyzed with the log-rank test. Differences in revision rates, including thrombolysis, thrombectomies, and operative revisions, were determined with the Fisher exact t test. RESULTS: Mean follow-up was 18 months (range, 4-24 months). For TAVFs, AVFs, and AVGs, primary functional patency rate at 1 year was 76.2%, 53.3%, and 47.2%, respectively, and at 2 years was 67.7%, 34.4%, and 25.5%, respectively. Similarly, secondary functional patency rate at 1 year was 83.2%, 66.7%, and 58.5%, respectively, and at 2 years was 74.6%, 56.2%, and 40.2%, respectively. Primary and secondary functional patency rates for TAVFs were superior to those for AVGs at 1 and 2 years (P <.001). AVFs had superior secondary functional patency rate at 2 years, compared with AVGs (P <.05), and TAVFs had superior primary and secondary patency rates at 2 years, compared with AVFs (P <.05). AVGs required significantly more revisions than did TAVFs (28.5% vs 54.7%; P <.001) or AVFs (36.7% vs 54.7%; P <.05). CONCLUSIONS: Preoperative duplex scanning of upper arm and forearm veins facilitated successful creation of all types of autogenous fistulas at our institution. TAVF cumulative functional patency rates were superior compared with AVGs and AVFs. Furthermore, TAVFs and AVFs were more durable and required fewer revisions than did AVGs. When preoperative duplex criteria indicate that TAVFs can be performed, they should be the initial access of choice, because of their superior long-term patency and durability.

Altered proliferative responses of dermal fibroblasts to TGF-beta1 may contribute to chronic venous stasis ulcer.

PURPOSE: Venous ulcer fibroblasts demonstrate decreased proliferative responses to growth factor stimulation, suggesting cellular senescence. However, the role of chronic venous insufficiency (CVI) disease progression and extracellular matrix (ECM) proteins in agonist-induced cellular proliferation is ill-defined. We hypothesize that CVI-induced fibroblast proliferative resistance to growth factors worsens with disease progression and is regulated by the composition of ECM. METHODS: Fibroblast explants were isolated from biopsy specimens from two patients without CVI and 16 patients with CVI of the lower calf (LC) and lower thigh (LT) and stratified according to CEAP disease severity: non-CVI (NC; n = 2), class 2-3 (n = 5), class 4 (n = 5), class 5 (n = 3), and class 6 (n = 3). Proliferation experiments were standardized with a neonatal foreskin fibroblast cell line (HS68). A 10-day course and dose response experiment with 0, 0.5, 1.0, 2.5, 5, 10, and 20 ng/mL of transforming growth factor-beta(1) (TGF-beta(1)) demonstrated maximal cell proliferation at 5 ng/mL of TGF-beta(1) on day 4. Under these conditions, CVI dermal fibroblasts were challenged with and without TGF-beta(1) and evaluated for proliferative responses on plates coated with polystyrene, collagen, and fibronectin. RESULTS: No differences in unstimulated proliferation were observed in LT and LC fibroblasts from patients with class 2-3 disease and LT fibroblasts from patients with class 4 and 5 disease, compared with NC and HS68 cells. LC fibroblasts from patients with class 4 disease (P <.05) and class 5 disease (P <.001), and LC (P <.001), and LT fibroblasts from patients with class 6 disease (P <.001) proliferated to a lesser degree than did NC and HS68 cells. The diminished proliferation observed in class 4 LC cells was reversible with TGF-beta(1) stimulation (P <.004); however, class 5 and class 6 LC and LT fibroblasts did not respond to stimulation with TGF-beta(1). Collagen increased proliferation of HS68 cells with (P <.05) and without (P <.01) TGF-beta(1), compared with cells grown on polystyrene, but did not increase proliferative responses in NC or CVI fibroblasts with and without TGF-beta(1). Similarly, fibronectin increased proliferation of HS68 cells (P <.05) compared with cells grown on polystyrene, but did not alter proliferation in CVI fibroblasts. Fibronectin did seem to inhibit TGF-beta(1)-induced proliferation observed in class 4 LC cells. CONCLUSION: These data indicate that clinical disease progression correlates with cellular dysfunction. Fibroblasts from patients with class 2-3 disease retain their unstimulated and agonist- induced proliferative capacity, compared with NC and HS68 cells. The onset of inflammatory skin changes (class 4 and class 5 disease) diminishes agonist-induced proliferation, and ulcer formation (class 6 disease) severely inhibits it. In addition, the composition of ECM does not affect TGF-beta(1)-induced proliferation of fibroblasts in CVI.

Methicillin-resistant Staphylococcus aureus infection does not adversely affect clinical outcome of lower extremity amputations.

Methicillin-resistant Staphylococcus aureus was first identified in isolation in Europe during the 1960's. Now widespread throughout the world, infection with this organism has emerged as a major problem in surgical practice. However, it remains debatable whether MRSA is more virulent than methicillin-susceptible strains. We have reviewed our most recent 4-year experience of lower extremity amputations to examine the influence of MRSA and non-MRSA infection on clinical outcome. During the past 4 years, 165 patients underwent lower extremity amputation for SVS/ISCVS category III acute limb ischemia and grades II and III chronic limb ischemia. Forty-five had documented MRSA infection, while 57 patients had documented infection with other flora. All patients were treated with appropriate sensitivity-specific antibiotics and aggressive wound care. No significant differences were noted in the level of primary amputation required by the two groups. Similarly, no significant differences were noted in either number of revisions or revision to higher-level amputation, time to heal, hospital length of stay, or 30-day morbidity and mortality rates. Our results demonstrate that MRSA infection does not adversely affect clinical outcome in patients undergoing lower extremity amputations. Appropriate treatment of infections with sensitivity-specific antibiotics, thorough wound debridement, and aggressive wound monitoring should be routine in all patients, regardless of bacterial flora.

Does severe venous insufficiency have a different etiology in the morbidly obese? Is it venous?

OBJECTIVE: Chronic venous insufficiency (CVI) is the most common cause of leg ulcers. Patients with morbid obesity are remarkable for particularly recalcitrant ulcers. Because obesity is not specifically incorporated in CEAP or other venous scoring systems, we sought to characterize this group of patients more completely. METHODS: Patients with severe CVI (CEAP clinical class, 4, 5, and 6), and class III obesity (body mass index [BMI], >40) were reviewed. Findings from clinical and duplex ultrasound scan (DU) examinations were compared with the CEAP classification, its adjunctive venous clinical severity score, and sensory thresholds. RESULTS: A review of clinic records identified 20 ambulatory patients with a mean age of 62 years, a mean BMI of 52, and a mean weight of 164 kg (361 lbs); all but one had bilateral symptoms. No evidence of venous insufficiency was detected with DU in 24 of the 39 limbs. Although some valvular incompetence was detected with DU in 15 of 39 limbs, these abnormalities were widely dispersed between 28 sites; eight limbs had findings at only one site. Ulceration (mean area, 29 cm(2)) was present in 25 limbs and necessitated 7 months for healing; 13 (52%) recurred at least once during a mean observation period of 36 months. The mean sensory threshold of 5.21 exceeded current risk thresholds used in diabetic screening programs. The distribution of CEAP clinical class was C4 (n = 14), C5 (n = 14), and C6 (n = 11). Increasing CEAP class correlated with an increased mean BMI of 47, 52, and 56, respectively (P <.01). CEAP also correlated with a rising mean venous clinical severity score of 10, 11, and 15, respectively (P <.05). CONCLUSION: Patients with class III obesity had severe limb symptoms, typical of CVI, but approximately two thirds of the limbs had no anatomic evidence of venous disease. The association of increasing limb symptoms with increasing obesity suggested that the obesity itself contributes to the morbidity.

VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide.

We tested the hypothesis that VEGF regulates endothelial hyperpermeability to macromolecules by activating the ERK-1/2 MAPK pathway. We also tested whether PKC and nitric oxide (NO) mediate VEGF-induced increases in permeability via the ERK-1/2 pathway. FITC-Dextran 70 flux across human umbilical vein endothelial cell monolayers served as an index of permeability, whereas Western blots assessed the phosphorylation of ERK-1/2. VEGF-induced hyperpermeability was inhibited by antisense DNA oligonucleotides directed against ERK-1/2 and by blockade of MEK and Raf-1 activities (20 microM PD-98059 and 5 microM GW-5074). These blocking agents also reduced ERK-1/2 phosphorylation. The PKC inhibitor bisindolylmaleimide I (10 microM) blocked both VEGF-induced ERK-1/2 activation and hyperpermeability. The NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (200 microM) and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidiazoline-1-oxyl-3-oxide (100 microM) abolished VEGF-induced hyperpermeability but did not block ERK-1/2 phosphorylation. These observations demonstrate VEGF-induced hyperpermeability involves activation of PKC and NOS as well as Raf-1, MEK, and ERK-1/2. Furthermore, our data suggest that ERK-1/2 and NOS are elements of different signaling pathways in VEGF-induced hyperpermeability.