Outcomes for Angioplasty and Bypass Lower Limb Revascularisation Procedures for Limb Salvage in England: Findings From the Getting It Right First Time Programme.

OBJECTIVE: The aim of this study was to investigate outcomes for lower limb revascularisation for limb salvage within the National Health Service (NHS) in England. METHODS: This was a retrospective observational study of administrative data. Data were extracted from the Hospital Episodes Statistics database for England. Data were included for a seven year period (1 April 2011-31 March 2018 inclusive) for all patients aged ≥ 18 years receiving surgery for peripheral arterial occlusive disease. Data were extracted for patient age, sex and frailty level, the NHS trusts undertaking the procedure, the technique used (angioplasty, bypass, endarterectomy, or hybrid), the mode of admission (elective or emergency), the surgical speciality, the financial year of admission, length of hospital stay during the procedure, subsequent emergency re-admission, revascularisation procedures within 30 days and subsequent amputation and mortality within one year and within five years. The primary outcome was one year amputation free survival. For analysis, data were separated into diabetic and non-diabetic patients. Multilevel modelling was used to adjust for hierarchy and observed confounding when investigating outcomes. RESULTS: Data were available for 98 109 procedures across 124 hospital trusts. For non-diabetic patients (odds ratio 1.142, 95% confidence interval 1.068-1.222), one year amputation free survival was higher for angioplasty than for bypass. For diabetic patients, there was no difference in the primary outcome. One year amputation rates, 30 day emergency re-admission rates, and length of stay were all lower for angioplasty, and 30 day revascularisation rates were lower for bypass for both diabetic and non-diabetic patients. CONCLUSION: Outcomes were generally better for angioplasty than for bypass surgery for lower limb revascularisation for both diabetic and non-diabetic patients. The findings should be interpreted with caution given the likely different clinical presentations of those selected for each procedure. Future clinical trials may provide more definitive data.

Editor's Choice - Volume-Outcome Relationships in Elective Abdominal Aortic Aneurysm Surgery: Analysis of the UK Hospital Episodes Statistics Database for the Getting It Right First Time (GIRFT) Programme.

OBJECTIVE: To investigate whether a volume-outcome relationship exists for elective abdominal aortic aneurysm (AAA) surgery conducted within the National Health Service (NHS) in England. METHODS: This was an analysis of administrative data. Data were extracted from the Hospital Episodes Statistics database for England from April 2011 to March 2019 for all adult admissions for elective infrarenal AAA surgery. Data were extracted for the NHS trust and surgeon undertaking the procedure, the surgical technique used (open or endovascular), the financial year of admission, length of hospital and critical care stay during the procedure and subsequent emergency re-admissions (primary outcome) and deaths within 30 days. Multilevel modelling was used to adjust for hierarchy and confounding. RESULTS: A dataset of 31 829 procedures (8867 open, 22 962 endovascular) was extracted. For open surgery, lower trust annual volume was associated with higher 30 day emergency re-admission rates and higher 30 day mortality. For open surgery, lower surgeon annual volume was associated with higher 30 day mortality and length of hospital stay greater than the median. For endovascular surgery, lower surgeon annual volume was associated with not having an overnight stay in critical care. None of the other volume-outcome relationships investigated was significant. CONCLUSION: For elective infrarenal AAA surgery in the UK NHS, there was strong evidence of a volume-outcome relationship for open surgery. However, evidence for a volume-outcome relationship is dependent on the specific procedure undertaken and the outcome of interest.

Hypoxia in abdominal aortic aneurysm supports a role for HIF-1α and Ets-1 as drivers of matrix metalloproteinase upregulation in human aortic smooth muscle cells.

BACKGROUND/AIMS: We sought to determine whether hypoxia is an initiating factor in the matrix metalloproteinase-2 (MMP-2) up-regulation observed in abdominal aortic aneurysm (AAA) and whether hypoxia-inducible factor-1α (HIF-1α) or Ets-1 are mediating factors. METHODS: Human AAA and normal aorta were analysed for MMP-2, HIF-1α and Ets-1 by immunohistochemistry. Human aortic smooth muscle cell (HASMC) cultures exposed to experimental hypoxia were analysed for hypoxia-induced proteins using gelatin zymography and immunoblotting. Multiplex PCR was used to detect MMP-1, membrane-type (MT)-MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. RESULTS: AAA tissues expressed HIF-1α, MMP-2 and Ets-1 strongly within smooth muscle cells and inflammatory infiltrate of the tunica media. Up-regulated MMP-2 was detected in hypoxia-exposed HASMC (p < 0.05), with MMP-9 elevations after exposure to sequential O(2) decreases (p < 0.05). Immunoblotting confirmed HIF-1α, Ets-1, VEGF and MMP-2 are up-regulated in HASMC exposed to hypoxia (p < 0.05), while transcription for MMP-1, MT-MMP-1, MMP-9, MMP-2 and MMP-7 (p < 0.05) increased in hypoxic HASMCs. CONCLUSION: Hypoxia facilitates HIF-1α, Ets-1 and VEGF up-regulation in addition to driving enhanced secretion of MMP-2 and MMP-9 by HASMC. Enhanced transcription of factors relevant to aneurysmal disease in hypoxia indicates possible roles in disease progression and potential targets for therapeutic intervention.

Waiting times for carotid endarterectomy in UK: observational study.

OBJECTIVES: To assess timeliness of carotid endarterectomy services in the United Kingdom. DESIGN: Observational study with follow-up to March 2008. SETTING: UK hospitals performing carotid endarterectomy. PARTICIPANTS: UK surgeons undertaking carotid endarterectomy from December 2005 to December 2007. MAIN OUTCOME MEASURES: Provision and speed of delivery of appropriate assessments of patients; carotid endarterectomy and operative mortality; 30 day postoperative mortality. RESULTS: 240 (61% of those eligible) consultant surgeons took part from 102 (76%) hospitals and trusts. Of 9913 carotid endarterectomies recorded on hospital episode statistics, 5513 (56%) were included. Of the patients who underwent endarterectomy, 83% had a history of transient ischaemic attack or stroke. Of these recently symptomatic patients, 20% had their operation within two weeks of onset of symptoms and 30% waited more than 12 weeks. Operative mortality was 0.5% during the inpatient stay and 1.0% (95% confidence interval 0.7% to 1.3%) by 30 days. CONCLUSION: Only 20% of symptomatic patients had surgery within the two week target time set by the National Institute for Health and Clinical Excellence (NICE). Although operative mortality rates are comparable with those in other countries, some patients might experience disabling or fatal stroke while waiting for surgery and hence not be included in operative statistics. Major improvements in services are necessary to enable early surgery in appropriate patients in order to prevent strokes.

A review of endovascular management of abdominal aortic aneurysm.

Abdominal aortic aneurysm is a common finding in older men and is often asymptomatic, either being found incidentally or presenting with acute rupture. This article will discuss the current indications for treatment and the clinical evidence behind the options currently available.

Customized tapered stent-grafts in the endovascular management of internal iliac artery aneurysms: a useful adjunct to conventional endovascular options.

The endovascular exclusion of an isolated iliac artery aneurysm is recognized as a safe and favorable alternative to open surgical repair, with low associated morbidity and mortality. It has particular advantages in the treatment of internal iliac artery aneurysm (IIAA) given the technical difficulties associated with open surgical repair deep within the pelvis. We describe the use of customized tapered stent-grafts in the exclusion of wide-necked IIAA in five male patients considered high-risk for conventional surgical repair, in whom the common and external iliac artery morphology precluded the use of standard endovascular devices. In each case, IIAA outflow was selectively embolized and the aneurysm neck excluded by placement of a customized tapered stent-graft across the internal iliac artery origin. This technique was extremely effective, with 100% technical success, no serious associated morbidity, and zero mortality. In all five patients sac size was stable or reduced on computed tomography follow-up of up to 3 years (mean, 24.4 months), with a primary patency rate of 100%. We therefore advocate the use of customized tapered stent-grafts as a further endovascular option in the management of IIAA unsuitable for conventional endovascular repair.

GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery.

BACKGROUND: Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival. METHODS/DESIGN: A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free (including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00525237.

Vascular tissue engineering: bioreactor design considerations for extended culture of primary human vascular smooth muscle cells.

The influence of mechanical stimulation on cell populations not only helps maintain the specific cellular phenotype but also plays a significant role during differentiation and maturation of plastic cells. This is particularly true of tissue-engineered vascular tissue, where in vivo shear forces at the blood interface help maintain the function of the endothelium. Considerable effort has gone into the design and implementation of functional bioreactors that mimic the chemical and mechanical forces associated with the in vivo environment. Using a decellularized ex vivo porcine carotid artery as a model scaffold, we describe a number of important design criteria used to develop a vascular perfusion bioreactor and its supporting process-flow. The results of a comparative analysis of primary human vascular smooth muscle cells cultured under traditional"static conditions" and "dynamic loading" are described, where the expression of MMP-2 and 9 and cathepsin-L were assessed. Continued design improvements to perfusion bioreactors may improve cellular interactions, leading to constructs with improved biological function.

Differential expression of TRAIL and its receptors relative to calcification in AAA.

Abdominal aortic aneurysm (AAA) is commonly associated with atherosclerosis. Human AAA tissue displays cells undergoing all stages of apoptosis. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumour cells but not in normal cells. It has death receptors and decoy receptors. An inhibitor of TRAIL, osteoprotegerin (OPG), is involved in osteogenesis and vascular calcification. We investigated TRAIL and its receptors in AAA compared within normal aorta (NA). Both qualitative and quantitative analyses of calcification in AAA walls were determined using Von Kossa staining and pre-operation computer tomography (CT) scans. There was a significant difference in calcification level at different locations in the AAA wall (p <0.05). Apoptosis was confirmed in AAA by TUNEL assay. A significant difference in TRAIL and its receptor expression was observed between normal aortae and AAA (p<0.05). Significant differences were also observed between tissues displaying different extents of calcification for TRAIL mRNA (p<0.05) by RT-PCR examination and OPG protein (p<0.01) by protein blotting examination. We propose that this pattern of expression of TRAIL and its receptors may contribute to AAA formation and calcification in the AAA wall.

Porcine collagen crosslinking, degradation and its capability for fibroblast adhesion and proliferation.

Porcine dermal collagen permanently crosslinked with hexamethylene diisocyanate was investigated for its suitability as a dermal tissue engineering matrix. It was found that the chemically crosslinked collagen had far fewer free lysine groups per collagen molecule than did the uncrosslinked matrix. The ability of the matrix to support human primary fibroblast outgrowth from explants was compared for matrices that had been presoaked in various solutions, including fibroblast media, cysteine and phosphate buffered saline (PBS). It was found that superior cell outgrowth was obtained after soaking with fibroblast media and PBS. The fibroblast attachment properties of the matrix were compared against tissue culture plastic and PET. The collagen matrix showed the least amount of cell retention compared to the other to matrices, however, the general trends were similar for all three scaffolds. Longer term cultures on the collagen showed fibroblasts covering the matrix stacking up on each other and bridging natural hair follicles. However, it was also observed that the fibroblasts were not able to penetrate into the matrix structure. This was believed to result from the chemical crosslinking, as shown by the resistance of the matrix to degradation by collagenases.

Preparation of porcine carotid arteries for vascular tissue engineering applications.

Biomaterials derived from tissue continue to offer viable alternatives to synthetic materials when autologous materials are unavailable for transplantation due to their unique chemical and mechanical properties. Tissue processing aims to stabilize the material against host degradation and render it immunologically inert by removing cellular material and crosslinking the structural proteins. It is clear that different approaches taken to achieve these goals have very different chemical and mechanical effects on the material. We describe herein the development of a tissue processing methodology to generate acellular scaffolds for tissue engineering small-diameter vascular grafts. Carotid arteries were isolated from Great White pigs and exposed to various solvent treatments, xylene, butanol, and ethanol to determine optimal parameters for the extraction of host lipids. The tissue was then exposed to a limited proteolysis with trypsin to disrupt cellular protein. This resulted in a controlled digestion that disrupted porcine nuclear DNA and cleared bulk cellular protein, leaving the more resistant structural proteins largely intact and retaining the bulk mechanical properties of the matrix. Histological analysis and scanning electron microscopy illustrated the complete removal of intact cells and nuclear material. The decellularized graft was stabilized by crosslinking with the photooxidative dye methylene green in the presence of 30,000 LUX of broad-band light energy. High-performance liquid chromatography analysis showed that the crosslinked tissue yielded 78.6% less hydroxyproline, compared with control tissue, after 20 h incubation with pepsin. Analysis of the crosslinked vessels' burst-pressure and stress-strain characteristics have shown comparable mechanical properties to those of control vessels. Assessment of in vitro cell adhesion and compatibility was conducted by seeding primary human umbilical vein endothelial cells and adult human vascular smooth muscle cells onto the lumenal and ablumenal surfaces, respectively; these cells were shown to adhere and proliferate under traditional static culture conditions.

Endothelial and smooth muscle cell seeding onto processed ex vivo arterial scaffolds using 3D vascular bioreactors.

Biomaterials derived from ex vivo tissues offer a viable alternative to synthetic materials for organ replacement therapies. In this study, we describe the use of a tissue engineering scaffold derived from ex vivo arterial tissue to assess vascular cell adhesion within a three-dimensional perfusion bioreactor. With the aim of maximizing seeding efficiency, five methods for endothelial cell (EC) and three independent methods for vascular smooth muscle cell (VSMC) adhesion were explored. Seeded constructs were maintained in vascular bioreactors under pulsatile flow conditions, culminating at 165 ml/min at 1.33 Hz to validate cell attachment and retention over time. Progressive modification of the seeding and flow regime protocols resulted in an increased of EC retention from 5.1 to 634 cells/mm2. Seeding VSMCs as sheets rather than cell suspensions bound and stabilized surface EC matrix fibers, resulting in multiple cell layers adhered to the scaffold with cells migrating to the medial/adventitial boundary. In conjunction with the bioscaffold, the vascular perfusion system serves as a useful tool to analyze cell adhesion and retention by allowing controlled manipulation of seeding and perfusion conditions.