Faculty Bibliography

BACKGROUND: Venous outflow obstruction may play a role in patients with chronic venous stasis symptoms who fail to improve despite conventional modalities of treatment that focus on the reflux component of the disease with little attention to the possibility of an obstructive component. The introduction of minimally invasive venous stenting using venography and intravenous ultrasonography (IVUS) provides the ability to treat the "obstructive" component of the disease. METHODS: We undertook a retrospective review of 56 limbs in 53 patients with chronic venous stasis symptoms. Initial transcutaneous Doppler ultrasonographic evaluation of the inferior vena cava, iliac, femoral, greater saphenous, and perforator veins was performed looking for any evidence of deep venous thrombosis, superficial venous thrombosis, perforator veins, and reflux (location and degree). Afterword, the patients were managed in the conventional fashion (leg elevation, compression, and great saphenous vein (GSV) and perforator ablation, if present) for a period of 3 months. If ulcer healing was not noted, iliac-femoral venography and IVUS were undertaken. A significant stenosis was defined as a 50% reduction in vein cross-sectional area as measured by IVUS.(1,2,3) Stenotic lesions were managed with stenting followed by balloon angioplasty. Patients were followed up for ulcer healing or improvement of stasis symptoms. RESULTS: Of the 56 limbs, 10 (17.8%) had postthrombotic changes, 7 (12.5%) had incompetent perforators, and 27 (48.2%) had an incompetent superficial venous system. In the stented group (n = 29), 3 limbs had perforator ablation alone, 13 limbs had GSV ablation alone, and 1 limb had both perforator and GSV ablation. In the unstented group (n = 27), 10 limbs had GSV ablation alone, and 3 limbs had both perforator and GSV ablation. The overall incidence of deep reflux was 51.8%; 17 of 29 limbs (58.6%) in the stented group had evidence of deep reflux, and 12 of 27 limbs (44.4%) in the unstented group had deep reflux. All venograms except one (98.2%) were performed under local anesthesia with sedation. The procedure was performed in an ambulatory setting in 69.6% (39 of 56) of the limbs. CEAP clinical severity class distribution was as follows: C2, 4%; C3, 16%; C4, 18%; C5, 5%; C6, 57%. Over half of the limbs (29 of 56) were found to have stenotic lesions and required stenting. Eight patients (11 limbs) did not return for ulcer healing assessment. The majority (19 of 29) of limbs in the stented group had a CEAP of 6. Among the patients with CEAP 6 who returned for follow-up (n = 26), 7 had no evidence of stenosis and required no stenting. Only one of those (14.3%) healed his ulcers after 3 months (average follow-up of 4.8 months). The remainder 19 limbs were found to have stenotic lesions and underwent stenting. The ulcers healed in 11 of those (58%) over a period of 1 week to 8 months (average of 5 months), with average follow-up of 3.6 months (p = 0.08). The cumulative primary and secondary patency rates were 93.1% (27 of 29) and 100% (29 of 29), respectively. Two stent thromboses occurred within 4 weeks of the initial procedure. Both occurred in patients with postthrombotic obstruction. One patient developed a superficial femoral artery pseudoaneurysm. CONCLUSION: Over half of our patients with open ulcers had stenotic lesions. The ulcers healed in 58% of the stented limbs. That indicates that outflow obstruction may play a significant role in patients with chronic venous stasis symptoms, especially those with open ulcers who failed to respond to other treatment modalities. The procedure itself is relatively safe and simple and can be performed on an ambulatory basis.

PURPOSE: To investigate the molecular mechanisms that lead to inhibition of intimal hyperplasia (IH) following p53 gene therapy. METHODS: In vivo p53 gene transfer to balloon injured rat carotid arteries was performed by utilizing adenovirus. The relationship between p53, p21, retinoblastoma protein (Rb), B-cell lymphoma 2 (Bcl-2), Bax, and Bcl-x was examined by immunohistochemistry. Expression of cyclin D1, Fas/CD95, and poly(ADP-ribose)polymerase (PARP) was determined. RESULTS: Our data indicate increased expression of p53 in the nuclei of vascular smooth muscle cells (VSMCs) in the media (P < .01) compared with the controls. In the treated animals, Bax and Bcl-x, p21, and Rb were significantly upregulated (P < .01). Immunoreactivity to Bcl-2 was observed only in the neointima of untreated groups at 14 days. An increased presence of Fas and decreased expression of PARP was observed in the cytoplasm of the VSMCs of p53-treated animals. CONCLUSIONS: P53 gene transfer activated a battery of downstream effector genes whose products are directly involved in cell cycle arrest, DNA repair, and apoptosis.

OBJECTIVES: Despite advances in endovascular therapies, critical limb ischemia (CLI) continues to be associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. We sought to explore the feasibility of conducting a definitive trial of a bone marrow-derived cellular therapy for CLI in this "no option" population. METHODS: A pilot, multicenter, prospective, randomized, double-blind, placebo-controlled trial for "no option" CLI patients was performed. The therapy consisted of bone marrow aspirate concentrate (BMAC), prepared using a point of service centrifugation technique and injected percutaneously in 40 injections to the affected limb. Patients were randomized to BMAC or sham injections (dilute blood). We are reporting the 12-week data. RESULTS: Forty-eight patients were enrolled. The mean age was 69.5 years (range, 42-93 years). Males predominated (68%). Diabetes was present in 50%. Tissue loss (Rutherford 5) was present in 30 patients (62.5%), and 18 (37.5%) had rest pain without tissue loss (Rutherford 4). Patients were deemed unsuitable for conventional revascularization based on multiple prior failed revascularization efforts (24 [50%]), poor distal targets (43 [89.6%]), and medical risk (six [12.5%]). Thirty-four patients were treated with BMAC and 14 with sham injections. There were no adverse events attributed to the injections. Renal function was not affected. Effective blinding was confirmed; blinding index of 61% to 85%. Subjective and objective outcome measures were effectively obtained with the exception of treadmill walking times, which could only be obtained at baseline and follow-up in 15 of 48 subjects. This pilot study was not powered to demonstrate statistical significance but did demonstrate favorable trends for BMAC versus control in major amputations (17.6% vs 28.6%), improved pain (44% vs 25%), improved ankle brachial index (ABI; 32.4% vs 7.1%), improved Rutherford classification (35.3% vs 14.3%), and quality-of-life scoring better for BMAC in six of eight domains. CONCLUSIONS: In this multicenter, randomized, double-blind, placebo-controlled trial of autologous bone marrow cell therapy for CLI, the therapy was well tolerated without significant adverse events. The BMAC group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls. This pilot allowed us to identify several areas for improvement for future trials and CLI studies. These recommendations include elimination of treadmill testing, stratification by Rutherford class, and more liberal inclusion of patients with renal insufficiency. Our strongest recommendation is that CLI studies that include Rutherford 4 patients should incorporate a composite endpoint reflecting pain and quality of life.

In 2008, the Society for Vascular Surgery published guidelines for the treatment of carotid bifurcation stenosis. Since that time, a number of prospective randomized trials have been completed and have shed additional light on the best treatment of extracranial carotid disease. This has prompted the Society for Vascular Surgery to form a committee to update and expand guidelines in this area. The review was done using the GRADE methodology.[corrected] The perioperative risk of stroke and death in asymptomatic patients must be below 3% to ensure benefit for the patient. Carotid artery stenting (CAS) should be reserved for symptomatic patients with stenosis 50% to 99% at high risk for CEA for anatomic or medical reasons. CAS is not recommended for asymptomatic patients at this time. Asymptomatic patients at high risk for intervention or with <3 years life expectancy should be considered for medical management as first line therapy. In this Executive Summary, we only outline the specifics of the recommendations made in the six areas evaluated. The full text of these guidelines can be found on the on-line version of the Journal of Vascular Surgery at http://journals.elsevierhealth.com/periodicals/ymva.

Management of carotid bifurcation stenosis is a cornerstone of stroke prevention and has been the subject of extensive clinical investigation, including multiple controlled randomized trials. The appropriate treatment of patients with carotid bifurcation disease is of major interest to the community of vascular surgeons. In 2008, the Society for Vascular Surgery published guidelines for treatment of carotid artery disease. At the time, only one randomized trial, comparing carotid endarterectomy (CEA) and carotid stenting (CAS), had been published. Since that publication, four major randomized trials comparing CEA and CAS have been published, and the role of medical management has been re-emphasized. The current publication updates and expands the 2008 guidelines with specific emphasis on six areas: imaging in identification and characterization of carotid stenosis, medical therapy (as stand-alone management and also in conjunction with intervention in patients with carotid bifurcation stenosis), risk stratification to select patients for appropriate interventional management (CEA or CAS), technical standards for performing CEA and CAS, the relative roles of CEA and CAS, and management of unusual conditions associated with extracranial carotid pathology. Recommendations are made using the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system, as has been done with other Society for Vascular Surgery guideline documents.[corrected] The perioperative risk of stroke and death in asymptomatic patients must be <3% to ensure benefit for the patient. CAS should be reserved for symptomatic patients with stenosis of 50% to 99% at high risk for CEA for anatomic or medical reasons. CAS is not recommended for asymptomatic patients at this time. Asymptomatic patients at high risk for intervention or with <3 years life expectancy should be considered for medical management as the first-line therapy.

In 2006, the Society for Vascular Surgery began development of clinical practice guidelines to assist clinicians in the process of decision making. The Society selects clinical questions of high impact and evaluates the totality of evidence by identifying and conducting rigorous systematic reviews. Multidisciplinary committees follow the Grading of Recommendations, Assessment, Development and Evaluation framework (GRADE), standard consensus, and voting procedures. Factors other than evidence, including patients' values and preferences and the availability of surgical expertise, are also considered. We describe, in the context of cumulative 4-years' experience, the methods and rigor of current procedures adopted by the Society for Vascular Surgery in developing practice guidelines. We also discuss potential future efforts needed to maximize the quality, adoption, and application of the clinical recommendations.