Systematic review of inframalleolar endovascular interventions and rates of limb salvage, wound healing, restenosis, rest pain, reintervention and complications.

OBJECTIVES: Peripheral artery disease is estimated to affect 237 million individuals worldwide. Critical limb ischaemia, also known as chronic limb threatening ischaemia is a consequence of the progression of peripheral artery disease which occurs in ∼21% of patients over a five-year period. The aim of this systematic review is to assess the use of additional below-the-ankle angioplasty in comparison to the use of above-the-ankle angioplasty alone, and the subsequent rates of amputation, wound healing, restenosis, rest pain, reintervention and complications. METHODS: This systematic review was undertaken in accordance with PRISMA guidelines following a registered protocol (CRD42019154893). Online databases were searched using a search strategy of 20 keywords. Included articles reported the outcome for inframalleolar (pedal artery, pedal arch, plantar arteries) angioplasty with additional proximal angioplasty in comparison to proximal angioplasty alone. GRADE assessment was applied to assess the quality of the evidence. RESULTS: After screening 1089 articles, 10 articles met the inclusion criteria. Comparative performance assessment of below-the-ankle with above-the-ankle versus above-the-ankle angioplasty alone was undertaken in 3 articles, with the remaining 7 articles reporting outcomes of below-the-ankle with above-the-ankle angioplasty with no distinct comparator group. Significant decrease in major lower limb amputation at the last follow-up in the below-the-ankle group when compared with the above-the-ankle angioplasty alone group was observed in a single study (3.45% vs. 14.9%, p < 0.05). Improved wound healing rate at follow-up in the below-the-ankle group versus above-the-ankle angioplasty alone group was also reported in a single study (59.3% vs. 38.1%, p < 0.05). Subsequent rate of amputation after below-the-ankle angioplasty has been estimated as 23.5%. CONCLUSION: To date, there is a lack of studies assessing inframalleolar interventions and their use in improving limb salvage, wound healing and symptomatology. Prospective RCTs should be undertaken with adequate participant numbers to be sufficiently powered and report clinically important end-points.

Effect of footplate neuromuscular electrical stimulation on functional and quality-of-life parameters in patients with peripheral artery disease: pilot, and subsequent randomized clinical trial.

BACKGROUND: Supervised exercise programmes for intermittent claudication have poor access and limited compliance. Neuromuscular electrical stimulation (NMES) may be an effective alternative. A proof-of-concept study and RCT were conducted. METHODS: In study 1, eligible patients underwent baseline assessment; treadmill testing for initial (ICD) and maximum (MCD) claudication distance; EuroQoL Five Dimensions five-level instrument (EQ-5D-5L™) and Intermittent Claudication Questionnaire (ICQ) assessment; and measurement of ultrasound haemodynamics of the superficial femoral artery. After familiarization with the NMES device, participants underwent a 30-min session of stimulation with concomitant recording of haemodynamic measures at 15 min, and after device cessation. Measurements were repeated after 6 weeks of daily use of NMES. In study 2, consecutive patients underwent baseline assessment before online randomization to a supervised exercise programme only, or adjunctive NMES treatment for 6 weeks, followed by repeat measurements. RESULTS: Study 1 (20 patients) showed a significant improvement in MCD (46 per cent; P < 0·001) and ICD (71 per cent; P < 0·001). The RCT (42 patients) showed a significant adjunctive benefit of NMES in ICD (46 per cent; P = 0·014). Improvements were seen in the ICQ (9 points; P = 0·009) and EQ-5D-5L™ (P = 0·007) in study 1, and there was a significant adjunctive benefit of NMES on the ICQ score in patients who did supervised exercise (11·2 points; P = 0·031). Blood volume flow and time-adjusted mean velocity increased significantly with the device on (P < 0·050). Overall, NMES compliance exceeded 95 per cent. CONCLUSION: Footplate NMES significantly improved walking distance in patients with intermittent claudication when used independently and also as an adjunct to supervised exercise. Registration number: trial 1, NCT02436200; trial 2, NCT02429310 (http://www.clinicaltrials.gov).

ANTECEDENTES: Los programas de ejercicio supervisado (supervised exercise programmes, SEP) para la claudicación intermitente (intermittent claudication, IC) tienen un acceso y un cumplimiento deficientes. La estimulación eléctrica neuromuscular (neuromuscular electrical stimulation, NMES) puede ser una alternativa clínicamente efectiva. Se realizó un estudio de prueba de concepto y un ensayo controlado aleatorizado. MÉTODOS: Estudio 1: Veinte pacientes elegibles se sometieron a una evaluación inicial que incluía una prueba en la cinta de correr para la distancia inicial de claudicación (initial claudication distance, ICD) y la distancia máxima de claudicación (maximum claudication distance, MCD), EuroQoL-5D (EQ-5D), valoración mediante el cuestionario de claudicación intermitente (intermittent claudication questionnaire, ICQ), y hemodinámica por ecografía de la arteria femoral superficial. Después de familiarizarse con el dispositivo NMES, los participantes se sometieron a una sesión de estimulación de 30 minutos con el registro concomitante de medidas hemodinámicas a los 15 minutos y después del cese del dispositivo. Se realizaron mediciones repetidas después de 6 semanas de uso diario de NMES. Estudio 2: Se reclutaron 42 pacientes que tras una evaluación inicial y posterior aleatorización al azar en línea, se asignaron al Grupo A, utilizando SEP solamente; o al el Grupo B, con tratamiento NMES complementario durante 6 semanas seguido de medidas repetidas. RESULTADOS: El estudio 1 mostró una mejoría significativa de la MCD (46%, P < 0,0001) y de la ICD (71%, P < 0.004). El ensayo clínico mostró un beneficio coadyuvante significativo de NMES en la ICD (46%, P = 0,014). Se observaron mejorías en la puntuación del ICQ (9 puntos, P < 0,01) y del EQ-5D (P < 0,05) en el estudio 1, con un beneficio coadyuvante significativo de NMES en la puntuación del ICQ (11 puntos, P < 0,05). El flujo de volumen de sangre (CC/min) y TAMV (cm/s) aumentaron significativamente con el dispositivo en funcionamiento (P < 0,05). El cumplimiento global de la NMES superó el 95%. CONCLUSIÓN: La plataforma de NMES para el pie mejora significativamente las distancias de caminar en la claudicación intermitente cuando se usa de forma independiente y también proporciona un beneficio complementario al ejercicio supervisado en la distancia caminada sin dolor. La mejora del flujo sanguíneo puede ser un mecanismo para explicar estos resultados.

Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration.

BACKGROUND: Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. METHODS: This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. RESULTS: After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. CONCLUSION: Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Truncal varicose vein diameter and patient-reported outcome measures.

BACKGROUND: Varicose veins and chronic venous disease are common, and some funding bodies ration treatment based on a minimum diameter of the incompetent truncal vein. This study assessed the effect of maximum vein diameter on clinical status and patient symptoms. METHODS: A prospective observational cohort study of patients presenting with symptomatic varicose veins to a tertiary referral public hospital vascular clinic between January 2011 and July 2012. Patients underwent standardized assessment with venous duplex ultrasonography, and completed questionnaires assessing quality of life (QoL) and symptoms (Aberdeen Varicose Vein Questionnaire, EuroQol Five Domain QoL assessment and EuroQol visual analogue scale). Clinical scores (Venous Clinical Severity Score (VCSS) and Clinical Etiologic Anatomic Pathophysiologic (CEAP) class) were also calculated. Regression analysis was used to investigate the relationship between QoL, symptoms and vein diameter. RESULTS: Some 330 patients were assessed before surgery. The median maximum vein diameter was 7·0 (i.q.r. 5·3-9·2) mm overall, 7·9 (6·0-9·8) mm for great saphenous vein and 6·0 (5·2-8·9) mm for small saphenous vein. In linear regression analysis, vein diameter was shown to have a significant association with VCSS (P = 0·041). For every 1-mm increase in vein diameter, there was a 2·75-fold increase in risk of being in CEAP class C4 compared with C2. No other QoL or symptom measures were related to vein diameter. CONCLUSION: Incompetent truncal vein diameter was associated with increasing VCSS, but not a variety of other varicose vein disease-specific and generic patient-reported outcome measures.

Nutcracker Syndrome: An Update on Current Diagnostic Criteria and Management Guidelines.

BACKGROUND: Nutcracker syndrome (NCS) describes left renal vein compression between the superior mesenteric artery and the aorta. Although uncommon, it is an important diagnosis due to the important morbidity associated with it, including the risk of chronic kidney disease from long-term left renal vein (LRV) hypertension and the risk of LRV thrombosis. METHODS: This article reviews the literature on NCS, particularly with respect to the diagnostic accuracy of different imaging modalities and the success rates, complications, and long-term follow-up data associated with various surgical interventions. RESULTS AND DISCUSSION: The diagnosis of this condition is based on a stepwise work-up with history and clinical examination, followed by Doppler ultrasonography, computed tomography, magnetic resonance imaging, intravascular ultrasound (IVUS) and phlebography with measurement of the renocaval pressure gradient. Management is determined by symptom severity; often symptom resolution occurs following a conservative approach. However, in some cases, surgical management is required, particularly when conservative management is unsuccessful. When it comes to the surgical management of NCS three main pathways exist: open surgery, laparoscopic surgery and endovascular approaches, with the latter 2 becoming increasingly popular due to their minimal invasiveness. Additionally, cases involving the use of robotic surgery in the management of NCS have been reported. CONCLUSION: Despite the rarity of NCS, its recognition and management are important. This article has explored the evidence basis for conservative, medical and surgical options.

Deep Venous Procedures Performed in the National Health Service in England between 2005 and 2015.

OBJECTIVES: Recent advances in imaging technology and endovenous interventions have revolutionised the management of specific groups of patients with deep venous pathology. This study aimed to examine data published by Hospital Episode Statistics (HES) to assess trends in the number of endovascular and open surgical deep venous procedures performed in National Health Service (NHS) hospitals in England between 2005 and 2015. MATERIALS AND METHODS: The main diagnosis of deep venous thrombosis (DVT), and total number of primary open and percutaneous procedures for deep venous pathology for patients admitted to the NHS hospitals in England from 2005 to 2015 were retrieved from the HES database and analysed. RESULTS: An overall declining trend in the annual number of admissions for a primary diagnosis of DVT was observed (linear regression r2 = 0.9, p < .0001). The number of open surgical procedures for removal of thrombus remained largely unchanged (range 26-70); the frequency of percutaneous procedures increased steadily over the study period (range 0-311). The number of open surgical procedures relating to the vena cava fell between 2005 and 2009, and remained around 50 per year thereafter. Annual numbers of cases of deep venous bypass (range 17-33) and venous valve surgery (range 8-47) remained similar in trend over this period. The number of vena cava stent (range 0-405), other venous stent (range 0-316), and percutaneous venoplasty (range 0-972) procedures increased over the first 5 years of the study period. CONCLUSIONS: There is an increasing trend in relation to endovenous procedures but not open surgery, being carried out for deep venous pathology in the last decade in NHS hospitals in England. Despite a number of limitations with HES, the increase in the number of endovenous procedures shown is likely to have significant implications for the provision of care and healthcare resources for patients with deep venous pathology.

Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease.

OBJECTIVES: Chronic venous disease (CVD) is common, affecting a quarter of the population. Current conservative methods of treatment aim to prevent progression of disease by reducing ambulatory venous pressure. Neuromuscular electrical stimulation (NMES) refers to the use of electrical impulses to elicit muscle contraction. This pilot randomised controlled trial investigates the effect of a footplate NMES device (REVITIVE) on venous flow parameters, limb oedema, and quality of life outcome measures in patients with CVD. METHODS: Twenty-two patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2-C4 venous disease were randomised to receive a sham or test device. The recommended duration of use was for 30 minutes daily for 6 weeks. Venous flow parameters (duplex ultrasound), limb volume (optoelectric volumeter), and quality of life outcome measures were measured at baseline and after 6 weeks. RESULTS: The mean age of participants was 62 years, body mass index 28.6, with a 15:7 female preponderance. There was a significant difference in the percentage change in femoral vein flow parameters (from baseline) between the test and sham group while using the device (Week 0 time-averaged mean velocity 102.4% vs. -9.1%, p < .0001; volume flow 107.9% vs. -3.7%, p < .0001; peak velocity 377.7% vs. -6.7%, p < .0001). Limb volume was observed to increase significantly in the sham group (2.0% at Week 0 and 1.2% at Week 6; p < .01). This was prevented in the test group (+0.8% at Week 0 and 1.0% at Week 6; p = .06). There was a significant difference in the Aberdeen Varicose Vein Questionnaire between the two groups over the 6 weeks. CONCLUSIONS: This trial demonstrated a significant difference in venous flow parameters and prevention of orthostatic limb oedema with NMES. There was a positive effect on quality of life. Larger studies are required to determine the clinical significance of this in patients with venous disease.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Non-Invasive Management of Peripheral Arterial Disease.

BACKGROUND: Peripheral arterial disease (PAD) is common and symptoms can be debilitating and lethal. Risk management, exercise, radiological and surgical intervention are all valuable therapies, but morbidity and mortality rates from this disease are increasing. Circulatory enhancement can be achieved using simple medical electronic devices, with claims of minimal adverse side effects. The evidence for these is variable, prompting a review of the available literature. METHODS: Embase and Medline were interrogated for full text articles in humans and written in English. Any external medical devices used in the management of peripheral arterial disease were included if they had objective outcome data. RESULTS: Thirty-one papers met inclusion criteria, but protocols were heterogenous. The medical devices reported were intermittent pneumatic compression (IPC), electronic nerve (NMES) or muscle stimulators (EMS), and galvanic electrical dressings. In patients with intermittent claudication, IPC devices increase popliteal artery velocity (49-70 %) and flow (49-84 %). Gastrocnemius EMS increased superficial femoral artery flow by 140 %. Over 4.5-6 months IPC increased intermittent claudication distance (ICD) (97-150 %) and absolute walking distance (AWD) (84-112 %), with an associated increase in quality of life. NMES of the calf increased ICD and AWD by 82 % and 61-150 % at 4 weeks, and 26 % and 34 % at 8 weeks. In patients with critical limb ischaemia IPC reduced rest pain in 40-100 % and was associated with ulcer healing rates of 26 %. IPC had an early limb salvage rate of 58-83 % at 1-3 months, and 58-94 % at 1.5-3.5 years. No studies have reported the use of EMS or NMES in the management of CLI. CONCLUSION: There is evidence to support the use of IPC in the management of claudication and CLI. There is a building body of literature to support the use of electrical stimulators in PAD, but this is low level to date. Devices may be of special benefit to those with limited exercise capacity, and in non-reconstructable critical limb ischaemia. Galvanic stimulation is not recommended.

A Review of the Evidence to Support Neuromuscular Electrical Stimulation in the Prevention and Management of Venous Disease.

INTRODUCTION: The prevention and management of venous disease is a therapeutic challenge. Movement of blood through the venous system is augmented by the action of muscles on the deep veins, and can be achieved through the application of electrical current. The efficacy of currently available clinical devices for this purpose is unknown, and is investigated here. METHODS: A literature search of the EMBASE and Medline databases was performed, and studies were included if they were full text articles, written in english, pertaining to venous disease and neuromuscular electrical stimulation (NMES). RESULTS: NMES devices increase venous haemodynamic parameters such as peak velocity and volume flow. Studies report them to be non-inferior to intermittent pneumatic compression. They are effective in the prevention of venous thromboembolism, though inferior to low molecular weight heparin. NMES can reduce symptoms of chronic venous disease. DISCUSSION: NMES is an important tool in the prevention and management of venous disease, and avoids the significant risks associated with heparin administration. Data explored here is heterogenous in device, protocol, and reported end-points, therefore should be interpreted with care. Long term effects of treatment with NMES have not been explored.

Factors impacting on patient perception of procedural success and satisfaction following treatment for varicose veins.

BACKGROUND: Patient-reported outcome measures (PROMs) have been collected from patients undergoing varicose vein treatments in the National Health Service since 2009. The aim of this retrospective cohort study was to examine PROMs for varicose vein interventions, characterizing factors that might predict patient-reported perception of procedural success and satisfaction. METHODS: Centrally compiled PROMs data for varicose vein procedures carried out from 2009 to 2011 were obtained from the Hospital Episode Statistics data warehouse for England. As data were not distributed normally, non-parametric statistical tests were employed. RESULTS: Data for 35 039 patient episodes (62·8 per cent women) were available for analysis. Some 23·4 per cent of patients reported a degree of anxiety or depression before treatment; a formal diagnosis of depression was present in 7·8 per cent. Quality of life, measured by generic EQ-5D-3L™ index and the Aberdeen Varicose Vein Questionnaire (AVVQ) improved after intervention by 11·7 per cent (0·77 to 0·86) and 40·1 per cent (18·95 to 11·36) respectively. No significant improvement was found in EQ-5D™ visual analogue scale scores. There was a significant improvement in self-perceived anxiety or depression after the intervention (P < 0·001, McNemar-Bowker test). Both preoperative and postoperative depression or anxiety had a statistically significant relationship with self-reported success and satisfaction (both P < 0·001, χ(2) test). CONCLUSION: This analysis of PROMs is evidence that treatment of varicose veins improves quality of life, and anxiety or depression. Preoperative and postoperative anxiety or depression scores impact on patient-perceived success and satisfaction rates.

Editor's Choice-- A Systematic Review of Endovenous Stenting in Chronic Venous Disease Secondary to Iliac Vein Obstruction.

OBJECTIVES: Deep endovenous stenting to relieve chronic venous disease (CVD) secondary to post-thrombotic or non-thrombotic iliac vein obstruction is becoming increasingly well described. However, current and adequately reported systematic reviews on the topic are lacking. This report aimed to produce a systematic review and meta-analysis of the available data, reported to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials databases and key references were searched. RESULTS: Sixteen studies were included (14 before-and-after studies, 1 controlled before-and-after study, and 1 case series) encompassing successful deep venous stenting in 2,373 and 2,586 post-thrombotic or non-thrombotic limbs and patients respectively. The data were too heterogeneous to perform a meta-analysis. There were significant improvements in validated measures of the severity of CVD and venous disease-specific quality of life. Persistent ulcer healing rates ranged from 56% to 100% in limbs that had often already failed conservative management. Primary and secondary stent patency ranged from 32% to 98.7% and 66%-96% respectively. The major complication rate ranged from 0 to 8.7% per stented limb. A GRADE assessment demonstrated the quality of the evidence for five outcomes to be "Very Low" and one to be "Low" (ulcer healing). CONCLUSIONS: The quality of evidence to support the use of deep venous stenting to treat obstructive CVD is currently weak. The treatment does however appear promising and is safe and should therefore be considered as a treatment option while the evidence base is improved.

Systematic Review and Meta-Analysis of Utility of Graduated Compression Stockings in Prevention of Post-Thrombotic Syndrome.

BACKGROUND: Up to 50% of patients develop post-thrombotic syndrome (PTS) following their first proximal deep vein thrombosis (DVT). This meta-analysis aims to evaluate the effectiveness of graduated compression stockings (GCS) in preventing PTS. METHOD: Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov were electronically searched from inception to January 2015 for studies investigating the effect of GCS in preventing PTS. All randomised control trials were considered for inclusion if they compared the efficacy of GCS (30-40 mmHg at the ankle) with either placebo or no stockings in adults with new proximal lower limb DVT. Methodological assessment, using the Cochrane Risk of Bias Tool, and data extraction was performed by two independent reviewers. The effect of GCS was expressed as the risk difference (RD). RESULTS: A total of 686 articles were screened. Three randomised controlled trials inclusive of 1,177 patients were eligible for inclusion. PTS developed in 49-70% of control patients at 5 years. High statistical heterogeneity was observed between trials (all PTS: I(2) = 0.94; severe PTS: I(2) = 0.79). The risk difference in PTS incidence between control and GCS arms varied from 0% to 39% between trials. In trials with a higher baseline prevalence of PTS, a visual trend towards more benefit with GCS was noted. CONCLUSION: Uncertainty because of sampling variability and heterogeneity was too high to conclude in favour or against an effect of wearing compression stockings in preventing PTS. An effect may be present for higher values of baseline risk. Further evidence is needed. Article history.

Metabolic Phenotypes of Carotid Atherosclerotic Plaques Relate to Stroke Risk: An Exploratory Study.

OBJECTIVE: Stroke is a major cause of death and disability. That three-quarters of stroke patients will never have previously manifested cerebrovascular symptoms demonstrates the unmet clinical need for new biomarkers able to stratify patient risk and elucidation of the biological dysregulations. In this study, the utility of comprehensive metabolic phenotyping is assessed to provide candidate biomarkers that relate to stroke risk in stenosing carotid plaque tissue samples. METHOD: Carotid plaque tissue samples were obtained from patients with cerebrovascular symptoms of carotid origin (n = 5), and from asymptomatic patients (n = 5). Two adjacent biological replicates were obtained from each tissue. Organic and aqueous metabolite extracts were obtained separately and analysed using two ultra performance liquid chromatography coupled to mass spectrometry metabolic profiling methods. Multivariate and univariate tools were used for statistical analysis. RESULTS: The two study groups demonstrated distinct plaque phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the two groups with a strong statistical significance (p = 10(-4)-10(-5)). Specifically, metabolites related to the eicosanoid pathway (arachidonic acid and arachidonic acid precursors), and three acylcarnitine species (butyrylcarnitine, hexanoylcarnitine, and palmitoylcarnitine), intermediates of the ß-oxidation, were detected in higher intensities in symptomatic patients. However, metabolites implicated in the process of cell death, a process known to be upregulated in the formation of the vulnerable plaque, were unaffected. CONCLUSIONS: Discrimination between symptomatic and asymptomatic carotid plaque tissue is demonstrated for the first time using metabolic profiling technologies. Two biological pathways (eicosanoid and ß-oxidation) were implicated in differentiating symptomatic from asymptomatic patients and will be further investigated. These results indicate that metabolic phenotyping should be further explored to investigate the chemistry of the unstable plaque, in the pursuit of candidate biomarkers for risk-stratification and targets for pharmacotherapeutic intervention.

Prolonged Mechanical Circumferential Stretch Induces Metabolic Changes in Rat Inferior Vena Cava.

OBJECTIVE/BACKGROUND: Circumferential stretch on the vein wall has been suggested as a potential etiological factor in the development of varicose veins. However, the influence of vein wall stretch on vein metabolism has not yet been explored. The aim of this study was to investigate the effect of short and prolonged mechanical stretch on vein wall metabolism. METHODS: Circular segments of inferior vena cava from male Sprague-Dawley rats were exposed to normal 0.5-g (nonstretched) or high 2-g (stretched) tension for short (4 h) or prolonged (18 h) duration (five vein segments per group). Contraction response to phenylephrine (10-5 M) and KCl (96 mM) was elicited to observe the effect of circumferential stretch on vein function. The polar and organic metabolites in vein tissue were extracted using a bilayer extraction method. Aqueous and organic extracts were analyzed using nuclear magnetic resonance spectroscopy and ultra performance liquid chromatography coupled to mass spectrometry, respectively. Data acquired from both analytical platforms were analyzed using mathematical modeling. RESULTS: Increased concentrations of valine (p = .02) and choline (p = .03) metabolites and triglyceride moieties (p = .03) were observed in veins stretched for 18 h compared with the nonstretched/18 h group. DISCUSSION: Increased concentrations of branched chain amino acid valine and cell membrane constituent choline indicate increased muscle breakdown and increased metabolism of membrane phospholipids under stretch in an ex-vivo model. Increased intensities of triglyceride moieties in stretched vein segments for 18 h suggest that high pressure may induce an inflammatory response. CONCLUSION: This study has shown that prolonged mechanical circumferential stretch (18 h) alters the metabolic profile of rat inferior vena cava.

Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence.

OBJECTIVE: In the past 20 years, research and clinical trials on the healing process of chronic wounds have highlighted the key role of the family of enzymes called matrix metalloproteinases (MMPs). If a strong correlation between the course of healing of chronic wounds and the levels of a biological marker can be demonstrated, then it may be possible to: i) identify the best marker threshold to predict the clinical evolution of the pathology; and ii) if causality has been found between the marker and pathology, to improve the healing outcome, to change the marker level. METHOD: The databases Medline and Embase were searched to identify clinical trials pertaining to the assessment of MMPs in chronic wounds with the following keywords 'metalloproteinase' or 'metalloprotease' and 'wound healing'. Clinical trials were considered for inclusion if they enrolled patients with cutaneous chronic wounds and were published in English. More than 50 clinical trials, consensus documents and guidelines were assessed for this review. RESULTS: MMPs play key roles in the wound healing process, and excessive expression and activation of some of these enzymes is seen in chronic cutaneous wounds where healing is delayed. Levels of MMPs are affected by a number of factors, including patient and wound characteristics. CONCLUSION: Levels of MMPs can be used to indicate the prognosis of chronic wounds and protease modulating treatments used to improve healing rates. DECLARATION OF INTEREST: The authors report no conflicts of interest in this work.

A Cost-effectiveness Analysis of Surgery, Endothermal Ablation, Ultrasound-guided Foam Sclerotherapy and Compression Stockings for Symptomatic Varicose Veins.

OBJECTIVE: The aim was to investigate the cost-effectiveness of interventional treatment for varicose veins (VV) in the UK NHS, and to inform the national clinical guideline on VV, published by the National Institute of Health and Care Excellence. DESIGN: An economic analysis was constructed to compare the cost-effectiveness of surgery, endothermal ablation (ETA), ultrasound-guided foam sclerotherapy (UGFS), and compression stockings (CS). The analysis was based on a Markov decision model, which was developed in consultation with members of the NICE guideline development group (GDG). METHODS: The model had a 5-year time horizon, and took the perspective of the UK National Health Service. Clinical inputs were based on a network meta-analysis (NMA), informed by a systematic review of the clinical literature. Outcomes were expressed as costs and quality-adjusted life years (QALYs). RESULTS: All interventional treatments were found to be cost-effective compared with CS at a cost-effectiveness threshold of £20,000 per QALY gained. ETA was found to be the most cost-effective strategy overall, with an incremental cost-effectiveness ratio of £3,161 per QALY gained compared with UGFS. Surgery and CS were dominated by ETA. CONCLUSIONS: Interventional treatment for VV is cost-effective in the UK NHS. Specifically, based on current data, ETA is the most cost-effective treatment in people for whom it is suitable. The results of this research were used to inform recommendations within the NICE guideline on VV.