A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. METHODS: Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689. FINDINGS: Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive). INTERPRETATION: In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy. FUNDING: UK National Institute of Health Research Health Technology Programme.

A pilot feasibility study of non-cultured autologous skin cell suspension for healing diabetic foot ulcers.

A prospective, single arm feasibility study was conducted to evaluate healing outcomes of DFUs treated with autologous skin cell suspension (ASCS) in combination with standard therapy. Wounds up to 100 cm2 in size that failed to heal with conventional therapy were included and wound healing, pain, exudate scores, Quality of Life, satisfaction scores, and safety outcomes were evaluated over a period of 26 weeks. Sixteen subjects were enrolled having a mean DFU duration of 60.4 weeks. All ulcers in this study had a positive healing trajectory, with a mean reepithelialization of 84.9% and 12.2 cm2 reduction in ulcer area. For ulcers that did not acquire a soft tissue infection post-treatment, all either healed or achieved ≥95% reepithelialization including some with exposed tendon. Improvements were observed in all aspects of the health-related Quality of Life questionnaire and subjects and clinicians were highly satisfied across all postoperative visits. This preliminary study suggests ASCS is a well-tolerated and promising therapy for the treatment of DFUs as all ulcers evaluated experienced positive healing results regardless of size, depth, and wound duration. Future studies are warranted to investigate ASCS compared to standard of care for all diabetic foot ulcers, inclusive of the evaluation of treatment algorithms and combination products.

Diabetic endothelial colony forming cells have the potential for restoration with glycomimetics.

Endothelial colony forming progenitor cell (ECFC) function is compromised in diabetes, leading to poor vascular endothelial repair, which contributes to impaired diabetic foot ulcer healing. We have generated novel glycomimetic drugs with protective effects against endothelial dysfunction. We investigated the effect of glycomimetic C3 on the functional capacity of diabetic ECFCs. ECFCs were isolated from healthy controls and patients with diabetes with neuroischaemic (NI) or neuropathic (NP) foot ulcers. Functionally, diabetic ECFCs demonstrated delayed colony formation (p < 0.02), differential proliferative capacity (p < 0.001) and reduced NO bioavailability (NI ECFCs; p < 0.05). Chemokinetic migration and angiogenesis were also reduced in diabetic ECFCs (p < 0.01 and p < 0.001), and defects in wound closure and tube formation were apparent in NP ECFCs (p < 0.01). Differential patterns in mitochondrial activity were pronounced, with raised activity in NI and depressed activity in NP cells (p < 0.05). The application of glycomimetic improved scratch wound closure in vitro in patient ECFCs (p < 0.01), most significantly in NI cells (p < 0.001), where tube formation (p < 0.05) was also improved. We demonstrate restoration of the deficits in NI cells but not NP cells, using a novel glycomimetic agent, which may be advantageous for therapeutic cell transplantation or as a localised treatment for NI but not NP patients.

Preventing and treating foot complications associated with diabetes mellitus.

Diabetes mellitus is associated with a series of macrovascular and microvascular changes that can manifest as a wide range of complications. Foot ulcerations affect ∼2-4% of patients with diabetes mellitus. Risk factors for foot lesions include peripheral and autonomic neuropathy, vascular disease and previous foot ulceration, as well as other microvascular complications, such as retinopathy and end-stage renal disease. Ulceration is the result of a combination of components that together lead to tissue breakdown. The most frequently occurring causal pathways to the development of foot ulcers include peripheral neuropathy and vascular disease, foot deformity or trauma. Peripheral vascular disease is often not diagnosed in patients with diabetes mellitus until tissue loss is evident, usually in the form of a nonhealing ulcer. Identification of patients with diabetes mellitus who are at high risk of ulceration is important and can be achieved via annual foot screening with subsequent multidisciplinary foot-care interventions. Understanding the factors that place patients with diabetes mellitus at high risk of ulceration, together with an appreciation of the links between different aspects of the disease process, is essential to the prevention and management of diabetic foot complications.

Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair.

OBJECTIVE: Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS: This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross-sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS: After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS: Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level.

Quality and readability of online patient information for abdominal aortic aneurysms.

OBJECTIVE: We assessed the quality and readability of patient information for abdominal aortic aneurysms (AAAs) on the World Wide Web, as accessed from the United Kingdom. METHODS: Web sites returned by a simple Web search using the three largest search engines by market share were objectively and subjectively assessed for quality and readability. The Internet search engines Google, Yahoo!, and Bing were interrogated for the term "abdominal aortic aneurysm" and the first 50 hits screened. Organization type and Health on the Net status were recorded. Each unique site containing AAA information was scored for quality using the University of Michigan Consumer Health Web site Evaluation Checklist by two authors, and readability was calculated using the Flesch Reading Ease (FRE) score. Subjective content assessment was also undertaken. RESULTS: Of 150 hits, 112 were relevant, with 55 unique sites for assessment. Overall, the FRE score was 39 (range, 29-47) and the Michigan score was 36 (range, 25-56), with good interobserver agreement (r(s) = 0.83; P = .01). Michigan and FRE scores were poorly correlated (r(s) = 0.064; P = .6). Sites containing discussion on the merits of endovascular/open repair and the concept of an intervention threshold had the highest Michigan scores (58.5 [50-59.75] vs 28 [13-36.5]; P < .001). Search engine ranking, Health on the Net status, country of origin, and organization type did not affect quality or readability. CONCLUSIONS: The current quality and readability of online patient information for AAAs is poor and requires significant improvement. Clinicians treating patients with AAAs should be aware of the limitations of the online "lay literature."

Markers of inflammation in men with small abdominal aortic aneurysm.

BACKGROUND: Markers of inflammation and fibrin turnover are elevated in individuals with a large (>55 mm) abdominal aortic aneurysm (AAA). Fibrin degradation generates D-dimer, known to possess multiple proinflammatory effects, and levels are elevated during early AAA development. This study characterized the plasma inflammatory response during early AAA pathogenesis to determine the effect of D-dimer levels. METHODS: The study compared 75 men with a small AAA (range, 30-54 mm) with 90 age-, sex-, and race-matched controls. Plasma interleukin-6 (IL-6), complement C3, high-sensitivity C-reactive protein (hsCRP), fibrinogen, and D-dimer levels were measured. RESULTS: Mean levels of fibrinogen (2.92 vs 2.59 g/L; P = .003), hsCRP (2.07 vs 1.29 ng/mL; P = .005), and D-dimer (346.7 vs 120.2 ng/mL; P < .001) were higher in men with a small AAA. These markers correlated with maximum aortic diameter determined by ultrasound imaging. On multivariate analysis, D-dimer levels were elevated in AAA individuals independent of smoking, cardiovascular disease (CVD), atherosclerotic risk factors, and inflammatory parameters. Fibrinogen and hsCRP levels remained elevated after adjustment for these covariates but lost significance when D-dimer was added to the model. CONCLUSION: C-reactive protein and D-dimer levels are elevated during early AAA development. D-dimer levels are most tightly associated with AAA status, however, and may mediate the observed elevation in acute-phase reactants.

The use of animal models in developing the discipline of cardiovascular tissue engineering: a review.

Cardiovascular disease remains one of the major causes of death and disability in the Western world. Tissue engineering offers the prospect of being able to meet the demand for replacement of heart valves, vessels for coronary and lower limb bypass surgery and the generation of cardiac tissue for addition to the diseased heart. In order to test prospective tissue-engineered devices, these constructs must first be proven in animal models before receiving CE marking or FDA approval for a clinical trial. The choice of animal depends on the nature of the tissue-engineered construct being tested. Factors that need to be considered include technical requirements of implanting the construct, availability of the animal, cost and ethical considerations. In this paper, we review the history of animal studies in cardiovascular tissue engineering and the uses of animal tissue as sources for tissue engineering.