Incidence and outcomes of sepsis after cardiac surgery as defined by the Sepsis-3 guidelines.

BACKGROUND: The Sepsis-3 guidelines diagnose sepsis based on organ dysfunction in patients with either proven or suspected infection. The objective of this study was to assess the incidence and outcomes of sepsis diagnosed using these guidelines in patients in a cardiac intensive care unit (CICU) after cardiac surgery. METHODS: Daily sequential organ failure assessment (SOFA) scores were calculated for 2230 consecutive adult cardiac surgery patients between January 2013 and May 2015. Patients with an increase in SOFA score of ≥2 and suspected or proven infection were identified. The length of CICU stay, 30-day mortality and 2-yr survival were compared between groups. Multivariable linear regression, multivariable logistic regression, and Cox proportional hazards regression were used to adjust for possible confounders. RESULTS: Sepsis with suspected or proven infection was diagnosed in 104 (4.7%) and 107 (4.8%) patients, respectively. After adjustment for confounding variables, sepsis with suspected infection was associated with an increased length of CICU stay of 134.1h (95% confidence interval (CI) 99.0-168.2, P<0.01) and increased 30-day mortality risk (odds ratio 3.7, 95% CI 1.1-10.2, P=0.02). Sepsis with proven infection was associated with an increased length of CICU stay of 266.1h (95% CI 231.6-300.7, P<0.01) and increased 30-day mortality risk (odds ratio 6.6, 95% CI 2.6-15.7, P<0.01). CONCLUSIONS: Approximately half of sepsis diagnoses were based on proven infection and half on suspected infection. Patients diagnosed with sepsis using the Sepsis-3 guidelines have significantly worse outcomes after cardiac surgery. The Sepsis-3 guidelines are a potentially useful tool in the management of sepsis following cardiac surgery.

Three-dimensional Ultrasound in the Management of Abdominal Aortic Aneurysms: A Topical Review.

Three-dimensional (3D) ultrasound is an evolving modality that may have numerous applications in the management of abdominal aortic aneurysms. Many vascular specialists will not be familiar with the different ways in which 3D vascular ultrasound data can be acquired nor how potential applications are being explored by researchers. Most of the current literature consists of small series and single-centre experience, although clinical themes such as measurement of abdominal aortic aneurysm volume and surveillance following endovascular repair are emerging. The aim of this topical review is to introduce clinicians to the current concepts of 3D ultrasound, review the current literature, and highlight avenues for further research in this new and exciting field of vascular imaging.

Cardiopulmonary exercise testing and survival after elective abdominal aortic aneurysm repair†.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is increasingly used in the preoperative assessment of patients undergoing major surgery. The objective of this study was to investigate whether CPET can identify patients at risk of reduced survival after abdominal aortic aneurysm (AAA) repair. METHODS: Prospectively collected data from consecutive patients who underwent CPET before elective open or endovascular AAA repair  (EVAR) at two tertiary vascular centres between January 2007 and October 2012 were analysed. A symptom-limited maximal CPET was performed on each patient. Multivariable Cox proportional hazards regression modelling was used to identify risk factors associated with reduced survival. RESULTS: The study included 506 patients with a mean age of 73.4 (range 44-90). The majority (82.6%) were men and most (64.6%) underwent EVAR. The in-hospital mortality was 2.6%. The median follow-up was 26 months. The 3-year survival for patients with zero or one sub-threshold CPET value ([Formula: see text] at AT<10.2 ml kg(-1) min(-1), peak [Formula: see text]<15 ml kg(-1) min(-1) or [Formula: see text] at AT>42) was 86.4% compared with 59.9% for patients with three sub-threshold CPET values. Risk factors independently associated with survival were female sex [hazard ratio (HR)=0.44, 95% confidence interval (CI) 0.22-0.85, P=0.015], diabetes (HR=1.95, 95% CI 1.04-3.69, P=0.039), preoperative statins (HR=0.58, 95% CI 0.38-0.90, P=0.016), haemoglobin g dl(-1) (HR=0.84, 95% CI 0.74-0.95, P=0.006), peak [Formula: see text]<15 ml kg(-1) min(-1) (HR=1.63, 95% CI 1.01-2.63, P=0.046), and [Formula: see text] at AT>42 (HR=1.68, 95% CI 1.00-2.80, P=0.049). CONCLUSIONS: CPET variables are independent predictors of reduced survival after elective AAA repair and can identify a cohort of patients with reduced survival at 3 years post-procedure. CPET is a potentially useful adjunct for clinical decision-making in patients with AAA.

3D contrast enhanced ultrasound for detecting endoleak following endovascular aneurysm repair (EVAR).

OBJECTIVE: CT angiography (CTA) for endovascular aneurysm repair (EVAR) surveillance involves irradiation and nephrotoxic X-ray contrast agents. Three-dimensional contrast enhanced ultrasound (3D CEUS) is a novel imaging technique that may be more sensitive to blood flow detection than CTA or 2D CEUS. 3D CEUS utilises positional information from magnetic field emitters to assemble all ultrasound reflections into a high-definition image. We compared 3D CEUS with CTA for the detection of endoleak and aneurysm expansion following EVAR. METHODS: 3D CEUS (Curefab), 2D CEUS (Philips IU22), and CTA were compared in 30-paired images from 23 patients. Sensitivity, specificity, positive, and negative predictive value were calculated for 2D and 3D CEUS against CTA as the 'gold standard'. Pearson correlation was used to compare aneurysm sac diameter. Data were analysed using SPSS version 19.0. RESULTS: 30 paired 3D CEUS and CTA images were analysed from 23 patients. Endoleaks were detected in 17 images with CTA, 18 on 2D CEUS, and 18 on 3D CEUS. The sensitivity, specificity, positive, and negative predictive values of 3D CEUS to detect endoleak were 100%, 92%, 94%, and 100%, respectively. There was excellent correlation (r=0.935; p≤.0001) between CTA and 3D CEUS for AAA sac diameter. Only 3D CEUS detected the inflow and outflow arteries in all 18 scans with endoleak. 2D CEUS detected the inflow in 16 (88.8%) and CTA on 12 (66.6%) of the images. CONCLUSION: 3D CEUS may be more sensitive to endoleak following EVAR than either 2D CEUS or CTA.

Comparison of three contemporary risk scores for mortality following elective abdominal aortic aneurysm repair.

OBJECTIVE/BACKGROUND: A number of contemporary risk prediction models for mortality following elective abdominal aortic aneurysm (AAA) repair have been developed. Before a model is used either in clinical practice or to risk-adjust surgical outcome data it is important that its performance is assessed in external validation studies. METHODS: The British Aneurysm Repair (BAR) score, Medicare, and Vascular Governance North West (VGNW) models were validated using an independent prospectively collected sample of multicentre clinical audit data. Consecutive, data on 1,124 patients undergoing elective AAA repair at 17 hospitals in the north-west of England and Wales between April 2011 and March 2013 were analysed. The outcome measure was in-hospital mortality. Model calibration (observed to expected ratio with chi-square test, calibration plots, calibration intercept and slope) and discrimination (area under receiver operating characteristic curve [AUC]) were assessed in the overall cohort and procedural subgroups. RESULTS: The mean age of the population was 74.4 years (SD 7.7); 193 (17.2%) patients were women and the majority of patients (759, 67.5%) underwent endovascular aneurysm repair. All three models demonstrated good calibration in the overall cohort and procedural subgroups. Overall discrimination was excellent for the BAR score (AUC 0.83, 95% confidence interval [CI] 0.76-0.89), and acceptable for the Medicare and VGNW models, with AUCs of 0.78 (95% CI 0.70-0.86) and 0.75 (95% CI 0.65-0.84) respectively. Only the BAR score demonstrated good discrimination in procedural subgroups. CONCLUSION: All three models demonstrated good calibration and discrimination for the prediction of in-hospital mortality following elective AAA repair and are potentially useful. The BAR score has a number of advantages, which include being developed on the most contemporaneous data, excellent overall discrimination, and good performance in procedural subgroups. Regular model validations and recalibration will be essential.

National risk prediction model for elective abdominal aortic aneurysm repair.

BACKGROUND: Mortality results for elective abdominal aortic aneurysm (AAA) repair are published by the Vascular Society of Great Britain and Ireland. These mortality results are not currently risk-adjusted. The objective of this study was to develop a national risk prediction model for elective AAA repair. METHODS: Data for consecutive patients undergoing elective AAA repair from the National Vascular Database between April 2008 and March 2011 were analysed. Multiple logistic regression and backwards model selection were used for model development. The study outcome measure was in-hospital mortality. Model calibration and discrimination were assessed for all AAA repairs, and separately for open repair and endovascular aneurysm repair (EVAR) subgroups. RESULTS: There were 312 in-hospital deaths among 11,423 AAA repairs (2.7 (95 per cent confidence interval (c.i.) 2.4 to 3.0) per cent): 230 after 4940 open AAA repairs (4.7 (4.1 to 5.3) per cent) and 82 after 6483 EVARs (1.3 (1.0 to 1.6) per cent). Variables associated with in-hospital death included in the final model were: open repair, increasing age, female sex, serum creatinine level over 120 µmol/l, cardiac disease, abnormal electrocardiogram, previous aortic surgery or stent, abnormal white cell count, abnormal serum sodium level, AAA diameter and American Society of Anesthesiologists fitness grade. The area under the receiver operating characteristic (ROC) curve was 0.781 (95 per cent c.i. 0.756 to 0.806) with a bias-corrected value of 0.774. Model calibration was good (P = 0.963) based on the Hosmer-Lemeshow goodness-of-fit test, (bias-corrected) calibration curves, risk group assessment and recalibration regression. CONCLUSION: This multivariable model for elective AAA repair can be used to risk-adjust outcome analyses and provide patient-specific estimates of in-hospital mortality risk for open AAA repair or EVAR.

Evaluation of five risk prediction models for elective abdominal aortic aneurysm repair using the UK National Vascular Database.

BACKGROUND: There is no consensus on the best risk prediction model for mortality following elective abdominal aortic aneurysm (AAA) repair. The objective was to evaluate the performance of five risk prediction models using the UK National Vascular Database (NVD). METHODS: Data on elective AAA repairs from the NVD between January 2008 and December 2010 were analysed. The models assessed were: Glasgow Aneurysm Score (GAS), Vascular Biochemical and Haematological Outcome Model (VBHOM), physiological component of the Vascular Physiological and Operative Severity Score for enUmeration of Mortality (V-POSSUM), Medicare and Vascular Governance North West (VGNW). Overall model discrimination and calibration in equally sized risk-group quintiles were assessed. RESULTS: The study cohort included 10,891 patients undergoing elective AAA repair (median age 74 years, 87.3 per cent men). The in-hospital mortality rates following endovascular and open repair were 1.3 and 4.7 per cent respectively (2.9 per cent overall). The Medicare and VGNW models both showed good discrimination (area under receiver operating characteristic (ROC) curve 0.71), whereas the GAS, VBHOM and V-POSSUM models showed poor discrimination (area under ROC curve 0.60, 0.61 and 0.62 respectively). The VGNW model was the only one to predict the overall mortality rate in the cohort (3.3 per cent predicted versus 2.9 per cent observed; P = 0.066). The VGNW model demonstrated good calibration, predicting risk accurately in four risk-group quintiles. The Medicare, V-POSSUM and VBHOM models accurately predicted risk in three, two and no risk-group quintiles respectively. CONCLUSION: The Medicare and VGNW models contain similar risk factors and showed good discrimination when applied to the NVD. Both models would be suitable for risk prediction after elective AAA repair in the UK.

Preoperative cardiopulmonary exercise testing and risk of early mortality following abdominal aortic aneurysm repair.

BACKGROUND: Cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capacity. The aim of this study was to assess whether preoperative CPET identifies patients at risk of early death following elective open and endovascular abdominal aortic aneurysm (AAA) repair. METHODS: Prospective data were collected from a pilot study between September 2005 and February 2007, and from all patients who underwent CPET before elective AAA repair at two vascular centres between February 2007 and November 2011. Symptom-limited, maximal CPET was performed on each patient. Univariable and multivariable analyses were used to identify risk factors for 30- and 90-day mortality. RESULTS: Some 415 patients underwent CPET before elective AAA repair. Anaerobic threshold (AT), peak oxygen consumption (peak V.O(2) ) and ventilatory equivalents for carbon dioxide were associated with 30- and 90-day mortality on univariable analysis. On multivariable analysis, open repair (odds ratio (OR) 4·92, 95 per cent confidence interval 1·55 to 17·00; P = 0·008), AT below 10·2 ml per kg per min (OR 6·35, 1·84 to 29·80; P = 0·007), anaemia (OR 3·27, 1·04 to 10·50; P = 0·041) and inducible cardiac ischaemia (OR 6·16, 1·48 to 23·07; P = 0·008) were associated with 30-day mortality. Anaemia, inducible cardiac ischaemia and peak V.O(2) less than 15 ml per kg per min (OR 8·59, 2·33 to 55·75; P = 0·005) were associated with 90-day mortality on multivariable analysis. Patients with two or more subthreshold CPET values were at increased risk of both 30- and 90-day mortality. CONCLUSION: An AT below 10·2 ml per kg per min, peak V.O(2) less than 15 ml per kg per min and at least two subthreshold CPET values identify patients at increased risk of early death following AAA repair.

Delayed carotid surgery: what are the causes in the north west of England?

INTRODUCTION: Carotid endarterectomy (CEA) should be performed within two weeks of symptoms for patients with carotid stenosis >50%. Whether these standards are being achieved and causes of delay between symptoms and CEA were investigated. DESIGN: An analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data for patients undergoing CEA between January-2006 and September-2010 were collected. Asymptomatic patients and those with no details on the timing of cerebral symptoms were excluded. METHODS: 'Delay' from symptom to CEA was defined as more than two weeks and 'prolonged-delay' more than eight weeks. Univariable and multivariable analyses were used to identify factors associated with these delays. RESULTS: Of 2147 patients with symptoms of cerebral ischaemia, 1522(70.9%) experienced 'delay' and 920(42.9%) experienced 'prolonged delay'. Patients with ischaemic heart disease were more likely to experience 'delay' (OR = 1.56; 95% CI 1.11-2.19, p = 0.011), whereas patients with stroke (OR = 0.77; 95%CI 0.63-0.94, p = 0.011) and those treated at hospitals with a stroke-prevention clinic (OR = 0.57; 95%CI 0.46-0.71, p < 0.001) were less likely to experience 'delay'. Patients treated after the publication of National Institute for Health and Clinical Excellence (NICE) guidelines were less likely to experience 'prolonged delay' (OR = 0.77; 95%CI 0.65-0.91, p = 0.003) but not 'delay'. CONCLUSION: Few patients achieved CEA within two weeks of symptoms. Introducing stroke-prevention clinics with one-stop carotid imaging appears important.

What are the risk factors for renal failure following open elective abdominal aortic aneurysm repair?

OBJECTIVES: Renal failure following abdominal aortic aneurysm (AAA) repair is a common and significant complication. The objective of this study was to identify risk factors for renal failure following open elective AAA repair. DESIGN: A retrospective analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data on patients undergoing open elective AAA repair were collected between January 2000 and December 2010. Patients with pre-operative serum creatinine >200 µmol/L were excluded. METHODS: Renal failure was reported by clinicians and included all patients requiring post-operative renal-replacement therapy. Univariate and multivariate analyses were used to identify renal failure risk factors. A simplified clinical risk score was developed. RESULTS: Post-operative renal failure occurred in 140 (6.0%) of 2347 patients and was associated with age >75 (OR = 1.58, 95%CI 1.11-2.26), symptomatic AAA (OR = 1.77, 95%CI 1.24-2.52), supra/juxta renal AAA (OR = 2.17, 95%CI 1.32-3.57) pre-operative serum creatinine >150 (OR = 2.75, 95%CI 1.69-4.50), treated hypertension (OR = 1.87, 95%CI 1.28-2.74), and respiratory disease (OR = 2.08, 95%CI 1.45-2.97). Patients with post-operative renal failure had significantly higher 30-day mortality (35.0% vs. 4.3%, p < 0.001). CONCLUSIONS: Renal failure following open elective AAA repair was associated with an increased risk of mortality. Risk factors for post-operative renal failure were identified and a simple clinical risk score developed to facilitate focussed care strategies for high-risk patients.

Ultrasound measurement of aortic diameter in a national screening programme.

OBJECTIVE: Currently there is no universally accepted standard for ultrasound measurement of abdominal aortic aneurysm (AAA). The aim was to investigate the reliability and reproducibility of inner to inner (ITI) versus outer to outer (OTO) ultrasound measurement of AAA diameter. METHODS: A prospective study design was used to collect 60 random images of aorta (1.4-7.1 cm). Inner and outer wall diameter measurements were then performed by 13 qualified AAA screening technicians and 11 vascular sonographers. RESULTS: The mean (range) diameter for all 60 aortas by ITI was 3.91 cm (1.39-6.80) and by OTO was 4.18 cm (1.63-7.09), a significant mean difference of 0.27 cm (95% CI: 0.23-0.32 cm). The reproducibility coefficients for differences between technicians were 0.30 cm (95% CI: 0.24-0.36) for ITI and 0.42 cm (95% CI: 0.35-0.49) for OTO indicating significantly better repeatability using ITI. Finally, 15 images were measured twice in random order by all screeners and sonographers. For AAAs > 5 cm, repeatability was significantly better with ITI than OTO (0.14 vs. 0.21; p = 0.016). CONCLUSION: There was the expected difference in AAA diameter between the two methods (0.27 cm). However, ITI wall method was measurably more reproducible.

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer.

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml(-1) has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin-antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group.

Alteration in platelet function in patients with early breast cancer.

The aim of this study was to examine our hypothesis that platelets of patients with breast cancer were functionally altered compared to healthy controls. The results have shown that the platelets from women with early breast cancer released significantly more vascular endothelial growth factor (VEGF) when stimulated with thrombin, tissue factor, clotting, or over a period of time. Similarly, release of thrombospondin (TSP) with thrombin and tissue factor was higher, but failed to reach a significant level. Thus, the observed differences in platelet response support our hypothesis, but warrant further work to determine the reason underlying the observed difference and potential clinical relevance of our findings.

Spatial distribution of mast cells in chronic venous leg ulcers.

Chronic venous leg ulcers (CVUs) show chronic inflammation but different pathological changes occur in different parts of the ulcer. There is a lack of re-epithelialisation and defective matrix deposition in the ulcer base but epidermal hyperproliferation and increased matrix deposition in the surrounding skin. The role of mast cells in wound healing, inflammation, fibrosis and epidermal hyperproliferation has been extensively studied but less is known about their role in CVUs. In the present study, we investigated the distribution of mast cells in CVUs with specific consideration of the differences between the ulcer base and the skin surrounding the ulcer. Both histochemical and immunohistological methods were used to detect the mast cell marker tryptase in frozen sections of CVU biopsies. Mast cells were counted in the dermis of normal skin, in the ulcer base and in the skin surrounding the ulcer. Double immunofluorescence staining was used to study the location of mast cells in relation to blood vessels. In normal skin few mast cells were seen in the dermis but none in the epidermis. However in CVUs there was a significant increase in intact and degranulated mast cells in the surrounding skin and ulcer edge (184 per field, p<0.003) of CVUs and a significant reduction in the ulcer base (20.5 per field p<0.05) in comparison to normal skin (61 per field). In CVUs mast cells showed a characteristic location near the epithelial basement membrane whilst mast cell granules and phantom cells (mast cells devoid of granules) were predominantly seen in the epidermis. In the dermis, mast cells were seen associated with blood vessels. The marked increase in mast cells in the surrounding skin of CVUs and depletion of mast cells in the ulcer base could implicate mast cell mediators in the pathological changes in CVUs particularly in the epidermal and vascular changes occurring in the surrounding skin.

Investigation of proposed mechanisms of chemotherapy-induced venous thromboembolism: endothelial cell activation and procoagulant release due to apoptosis.

UNLABELLED: Venous thromboembolism (VTE) during chemotherapy is common, with 7% mortality in metastatic breast cancer (MBC). In a prospective cohort study of patients with breast cancer, we investigated whether vascular endothelial cell activation (VECA), and whether apoptosis, is the cause of chemotherapy-induced VTE. METHODS: Serum markers of VECA, E-selectin (E-sel), vascular cell adhesion molecule 1 (VCAM-1) and d-dimer (fibrin degradation and hypercoagulability marker) were measured prechemotherapy and at 1, 4, and 8 days following chemotherapy. Clinical deep vein thrombosis (DVT) or pulmonary embolism and occult DVT detected by duplex ultrasound imaging were recorded as VTE-positive (VTE+). In patients with MBC, hypercoagulable response to chemotherapy was compared between patients with and without cancer progression. Development of VTE and cancer progression was assessed 3 months following starting chemotherapy. RESULTS: Of the 134 patients, 10 (7.5%) developed VTE (6 [17%] of 36 MBC receiving palliation, 0 of 11 receiving neoadjuvant to downsize tumor, and 4 [5%] of 87 early breast cancer receiving adjuvant chemotherapy, P = .06). Levels of E-sel and VCAM-1 decreased in response to chemotherapy (P < .001) in both VTE+ and patients not developing VTE (VTE-). However, decrease in VECA markers was similar in VTE+ and VTE- patients, implying this is not the cause of VTE. In patients with MBC following chemotherapy, d-dimer (geometric mean) increased by 36% in the 21 patients with MBC responding to chemotherapy but steadily decreased by 11% in the 15 who progressed (day 4, P < .01), implying patients with tumor response (apoptosis) had an early hypercoagulable response. CONCLUSIONS: During chemotherapy for breast cancer, VECA is induced; however, this is not the primary mechanism for VTE. Chemotherapy-induced apoptosis may enhance hypercoagulability and initiate VTE.

Venous ulcer fibroblasts compared with normal fibroblasts show differences in collagen but not fibronectin production under both normal and hypoxic conditions.

Previous immunocytochemical analysis showed that the base of venous ulcers was deficient in fibronectin compared with surrounding "normal" dermis. Here, we investigate whether impaired synthetic ability of ulcer fibroblasts could underlie this observation. Ulcer fibroblasts, established in culture from biopsies of the edge of chronic venous leg ulcers, were compared with normal fibroblasts grown from biopsies of site-and age-matched normal skin for their ability to synthesize matrix molecules. Collagen and fibronectin synthesis were measured following metabolic labeling, as collagenase susceptible counts and counts with gelatin affinity, respectively. More collagen was produced by normal fibroblasts than ulcer fibroblasts, both when the cells were cultured on plastic and in collagen gels. In fibronectin synthesis, however, there was no major difference between the two cell types on either substratum. The hypoxic environment to which ulcer fibroblasts are exposed may have caused the intrinsic differences in collagen synthesis by the two fibroblast types. When we tested the effect of culturing cells under hypoxic conditions, both cell types produced less collagen, especially normal fibroblasts grown in a collagen gel, but there was no effect of hypoxia on fibronectin synthesis. We conclude that venous ulcer edge-derived fibroblasts have an impaired ability to synthesize collagen in vitro, but synthesize fibronectin normally. Therefore, the low level of fibronectin found in venous ulcers is not likely to be due to the inability of ulcer cells to produce it or to the response to hypoxic conditions but may be due to the degradation of synthesized fibronectin by proteases present in these ulcers.

Differences in free and total tissue factor pathway inhibitor, and tissue factor in peripheral artery disease compared to healthy controls.

Tissue factor (TF) is one of the major initiators of coagulation and raised plasma levels have been found in various cardiovascular diseases. TF activity is, however, regulated by tissue factor pathway inhibitor (TFPI), and alteration in levels of TF and/or TFPI may thus relate to thrombogenesis and atherogenesis. To investigate possible abnormalities in TF and free TFPI (i.e. unbound to TF) and total TFPI among patients with peripheral artery disease (PAD), we studied 42 patients (mean age 57, 35 men) with objectively proven (by ABPI/Doppler) disease and 42 age- and sex- matched healthy controls. TF, free TFPI and total TFPI were measured in citrated plasma by ELISA. TF was higher in the patients with PAD compared to controls (275+/-122 pg/ml versus 158+/-60, P<0.0001) but levels of total TFPI were lower in the patients (43+/-10 ng/ml versus 50+/-15, P=0.021). There was no significant difference in levels of free TFPI between patients and controls (7.2+/-1.5 ng/ml in controls, 7.5+/-1. 6 among patients, P=0.39). Within the control patients, levels of free and total TFPI were significantly correlated (Spearman r=0.51, P=0.001) but in the patients with PAD this correlation was poor (r=0. 21, P=0.178). We suggest that reduced levels of total TFPI and raised levels of TF may contribute to the process of atherogenesis and the increased risk of thrombosis among patients with cardiovascular disease.

von Willebrand factor and soluble E-selectin in the prediction of cardiovascular disease progression in hyperlipidaemia.

Two specific endothelial cell products, von Willebrand factor and soluble E-selectin, were measured together with serum lipids, lipoprotein(a), systolic and diastolic blood pressure (SHP, DBP) in a follow up study of 162 patients attending a dedicated lipid clinic. Patients were further classified by the presence or absence of symptomatic vascular disease and smoking. After a mean of 49 months, 45 patients experienced a cardiovascular event (fatal or nonfatal myocardial infarction, stroke, or arterial surgery) and 11 developed non-cardiovascular diseases, including cancer. In univariate analysis, existing vascular disease (P < 0.01), increased levels of von Willebrand factor (P < 0.0001) and low density lipoprotein cholesterol (P < 0.02), greater age (P < 0.01), and lower levels of soluble E-selectin (P < 0.03) were all predictive of future vascular events. However, in multivariate analysis, only increased von Willebrand factor was predictive (P < 0.001). von Willebrand factor was also higher in patients who developed non-cardiovascular disease relative to those free of disease (P < 0.05). Our data support the hypothesis that increased levels of von Willebrand factor are an indicator of poor prognosis in patients with atherosclerosis or its risk factors.

The influence of acute smoking on leucocytes, platelets and the endothelium.

Cigarette smoking is a risk factor for the development of atherosclerosis. Possible mechanisms for this include leucocytes and platelet activation, and/or damage to the endothelium, any of which may contribute to changes in thrombosis and haemostasis. We examined the acute effects of smoking on these systems by obtaining blood before, immediately after, and at 10 and 30 min after the rapid smoking of two cigarettes in sequence by 20 smokers. Blood samples taken at the same time points from ten non-smokers acted as control material. In the smokers there was a transient rise in leucocyte count and neutrophil activation, but von Willebrand factor (VWF--marking endothelial damage) increased steadily at each time point (P <0.05). There were no changes in neutrophil elastase, soluble intercellular adhesion molecule-1 (sICAM-1 normally increased in smokers), fibrinogen, platelet count or soluble P-selectin (marking platelet activation, also normally increased in smokers). We conclude that the acute smoking of two cigarettes in succession will activate leucocytes and cause endothelial cell damage, but will not immediately influence platelet activity.

Adverse influence of cigarette smoking on the endothelium.

The effect of smoking on the blood vessel intima was examined by comparing indices of endothelial activity in serum from smokers with that from non-smokers. Serum from smokers contained higher levels of von Willebrand factor (p < 0.01), the smoking markers cotinine (p < 0.02) and thiocyanate (p < 0.01), and was more cytotoxic to endothelial cells in vitro (p < 0.02) than serum from non-smokers. The acute effects of smoking two unfiltered medium tar cigarettes was to briefly increase von Willebrand factor (p < 0.001) and cytotoxicity of serum to endothelial cells in vitro (p < 0.005), but lipid peroxides or thiocyanate were not increased by this short exposure to tobacco smoke. Although there were correlations between von Willebrand factor and smokers consumption of cigarettes (r = 0.28, p < 0.02), number of years smoking (r = 0.41, p < 0.001) and cotinine (r = 0.45, p < 0.01), the tissue culture of endothelial cells with physiological levels of thiocyanate or nicotine suggested that these two smoking markers were not cytotoxic. They are therefore unlikely to be directly responsible for increased von Willebrand factor in the serum of smokers. We suggest that smoking exerts a deleterious influence on the endothelium and that the mechanism is complex.