Validation of the Edinburgh Claudication Questionnaire in 1st generation Black African-Caribbean and South Asian UK migrants: a sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study.

BACKGROUND: We determined the diagnostic accuracy of the Edinburgh Claudication Questionnaire (ECQ) in 1st generation Black African-Caribbean UK migrants as previous diagnostic questionnaires have been found to be less accurate in this population. We also determined the diagnostic accuracy of translated versions of the ECQ in 1st generation South Asian UK migrants, as this has not been investigated before. METHODS: Subjects were recruited from the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study, a community based screening survey for heart failure in minority ethnic groups. Translated versions of the ECQ were prepared following a recognised protocol. All participants attending screening between October 2007 and February 2009 were asked to complete the ECQ in the language of their choice (English, Punjabi, Bengali, Urdu, Hindi or Gujarati). Subjects answering positively to experiencing leg pain or discomfort on walking were asked to return to have Ankle Brachial Pressure Index (ABPI) measured. RESULTS: 154 out of 2831 subjects participating in E-ECHOES (5.4%) were eligible to participate in this sub-study, for which 74.3% returned for ABPI assessment. Non-responders were younger than participants (59[9] vs. 65[11] years; p=0.015). Punjabi, English and Bengali questionnaires identified participants with Intermittent Claudication, so these questionnaires were assessed. The sensitivities (SN), specificities (SP), positive (PPV) and negative (NPV) predictive values were calculated. English: SN: 50%; SP: 68%; PPV: 43%; NPV: 74%. Punjabi: SN: 50%; SP: 87%; PPV: 43%; NPV: 90%. Bengali: SN: 33%; SP: 50%; PPV: 13%; NPV: 73%. There were significant differences in diagnostic accuracy between the 3 versions (Punjabi: 83.8%; Bengali: 45%; English: 62.2%; p<0.0001). No significant differences were found in sensitivity and specificity between illiterate and literate participants in any of the questionnaires and there was no significant different difference between those under and over 60 years of age. CONCLUSIONS: Our findings suggest that the ECQ is not as sensitive or specific a diagnostic tool in 1st generation Black African-Caribbean and South Asian UK migrants than in the Edinburgh Artery Study, reflecting the findings of other diagnostic questionnaires in these minority ethnic groups. However this study is limited by sample size so conclusions should be interpreted with caution.

Changes in health-related quality of life after ultrasound-guided foam sclerotherapy for great and small saphenous varicose veins.

BACKGROUND: Health-related quality of life (HRQOL) improves after superficial venous surgery for varicose veins, but the effect of ultrasound-guided foam sclerotherapy on HRQOL is unknown. The aim of this study was to determine changes in HRQOL after ultrasound-guided foam sclerotherapy for varicose veins. METHODS: Consecutive patients undergoing ultrasound-guided foam sclerotherapy for varicose veins were sent the Short Form 12 (SF-12) questionnaire, a generic measure of HRQOL, and the Aberdeen Varicose Vein Symptom Score (AVSS) questionnaire, a disease-specific measure of HRQOL, 1 week before treatment and 1, 6, and 12 months after treatment. RESULTS: The study enrolled 296 patients (34% male; 395 treated legs) with a median age of 57 years (range, 22-89 years). Of these, 24% had had previous superficial venous surgery, and 66% were CEAP C(2-3) (uncomplicated varicose veins). Questionnaire completion rates were 82%, 73%, and 69% at 1, 6, and 12 months after treatment. The median Physical Component Summary score of the SF-12 (higher score indicates better HRQOL) improved from 47.6 pretreatment to 49.4 at 1 month (P < .008, Wilcoxon signed rank test), to 51.9 at 6 months (P < .0005), and to 52.9 at 12 months (P < .0005). The median AVSS (lower score indicates better HRQOL) improved from 19.0 pretreatment to 16.5 at 1 month (P < .0005), to 8.7 at 6 months (P < .0005), and to 8.6 at 12 months (P < .0005). CONCLUSIONS: Ultrasound-guided foam sclerotherapy for great and small saphenous varicose veins leads to significant improvements in generic and disease-specific HRQOL for at least 12 months after treatment.

Peripheral arterial disease and Virchow's triad.

Peripheral arterial disease (PAD) is an important global healthcare problem associated with considerable morbidity and mortality. This disease is an important manifestation of atherosclerosis and the pathophysiological processes involved in its development, progression and complications are atherothrombosis and thromboembolism. Over 150 years ago, Virchow described a triad of abnormalities (abnormal blood flow, abnormal vessel wall and abnormal blood constituents) associated with thrombus formation (thrombogenesis). An improvement in biochemical techniques has allowed quantification of various components of Virchow's triad, and as a consequence, there has been increasing interest in the measurement of such biomarkers in understanding the development and progression of PAD, as well as its symptomatic complications. This review discusses quantifiable components of Virchow's triad that have been associated with PAD and their clinical utility as risk factors for PAD.

Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls.

BACKGROUND: Uncontrolled studies suggest that patients with chronic venous ulceration (CVU) have an increased prevalence of thrombophilia, similar to that observed in patients with deep vein thrombosis. This study compared the nature and prevalence of thrombophilia in patients with varicose veins (VV, CEAP clinical [C] grade C(2) to C(3)) and patients with CVU (C(5) to C(6)) with an age- and sex-matched population without clinical or duplex ultrasound evidence of venous disease. METHODS: Twenty-seven patients with VV, 27 patients with CVU, and 54 age- and sex-matched case controls with no clinical or duplex evidence of lower limb venous disease, underwent testing for factor V Leiden and prothrombin 20210A mutations, antithrombin deficiencies, and levels of antiphospholipid antibodies, homocysteine, protein C and S, and factor VIII, IX, and XI. RESULTS: The overall prevalences of single and multiple thrombophilias were significantly higher in cases than in controls. Specifically, in VV patients, the prevalences of no, single, and multiple thrombophilias were 33%, 52%, and 15%, respectively, compared with 63%, 26%, and 11% in VV controls. In CVU patients, the prevalences of no, single, and multiple thrombophilias was 26%, 30%, and 44%, respectively, compared with 66%, 22%, and 11% in CVU controls. Compared with controls, only factor XI levels were significantly higher in VV patients, and homocysteine and factor VIII, IX, and XI levels were all significantly higher in CVU patients. CONCLUSION: Patients with VV, and particularly CVU, have significantly higher prevalences of single and multiple thrombophilias than age- and sex-matched controls without clinical or duplex evidence of lower limb venous disease. These data support the hypothesis that thrombophilia predisposes to the development of superficial and deep lower limb venous reflux, and so VV and CVU, through the increased occurrence of clinical and subclinical thrombosis.

Surgical versus endovascular reconstruction for chronic mesenteric ischemia: a contemporary UK series.

OBJECTIVE: To assess the outcome of surgical (SR) and endovascular (ER) reconstruction for chronic mesenteric ischemia (CMI). METHODS: Retrospective review of consecutive patients who underwent SR or ER for CMI in 3 UK vascular surgery units between 1996 and 2006. Early (<30 days; technical success, morbidity, mortality, length of hospital stay) and late (>30 days) outcomes (symptom recurrence, vessel/graft patency, reintervention, mortality) were assessed. RESULTS: A total of 27 patients underwent 32 reconstructions (SR = 17, ER = 15). A total of 44 of 56 (79%) diseased arteries underwent SR (n = 26; bypass = 24, reimplantation = 2; occlusion = 16, stenosis = 10) or ER (n = 18; stenosis = 16, occlusion = 2). Perioperative mortality for SR and ER was 6% and 0%, respectively (P > or = .99). Hospital stay was shorter following ER (mean, 4.3 vs. 14.2 days, P = .0003). Mean (range) follow-up for SR and ER was 34 (1-94) and 34 (0-135) months, respectively. At 2 years, SR demonstrated superior secondary patency (100% vs. 65%) and clinical patency (100% vs. 73%). CONCLUSIONS: Surgical mesenteric reconstruction is associated with significantly longer hospital stay, but superior long-term outcome compared to endovascular reconstruction.

Thrombogenesis and endothelial damage/dysfunction in peripheral artery disease. Relationship to ethnicity and disease severity.

Peripheral artery disease (PAD) and intermittent claudication are common in men aged over 55 years. Once the diagnosis has been made, very few patients suffer from a deterioration of the disease. Those that do deteriorate tend to do so due to thrombosis of an affected artery. It is apparent that the disruption in the vessel wall accounts for some of the cause of the thrombosis but blood constituents also play a role. We hypothesized that levels of soluble P-selectin (sP-sel, a marker of platelet activation), von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, a coagulation protein involved in the 'extrinsic' coagulation pathway) and fibrinogen would be abnormally elevated in relation to disease severity and correlated with each other, and related to ethnicity, in a multiethnic population of patients with PAD. To test this hypothesis, we studied 234 patients (80% white, 7% Indo-Asian, 13% Afro-Caribbean) with confirmed PAD [ankle brachial pressure index (ABPI)< or =0.8] and 50 healthy controls. All of the indices studied were increased in patients over controls (p<0.05). None of the indices of the hypercoagulable state were significantly different between the three ethnic groups studied. Patients with ischaemic rest pain were shown to have higher levels of plasma fibrinogen (p<0.001) although none of the other prothrombotic markers were increased in this group. Furthermore, fibrinogen was higher in cases whose ABPI was below the median (<0.52) when compared to those less severely affected, with an inverse correlation between fibrinogen and ABPI (Spearman, r=-0.178, p=0.009). In conclusion, we found a prothrombotic state in patients with PAD with increased levels of markers of endothelial damage/dysfunction, platelet activation and thrombosis, which may contribute to the pathogenesis of this condition. However, disease severity was only related to plasma fibrinogen levels.

The role of monocytes in angiogenesis and atherosclerosis.

New vessel formation inside the arterial wall and atherosclerotic plaques plays a critical role in pathogenesis of heart attacks and strokes. The 2 known mechanisms resulting in the formation of new vessels within the plaque are local ischemia and inflammation. Blood monocytes play an important role in both processes. First, they express receptors for vascular endothelial growth factor and some of them may serve as circulating ancestors of endothelial cells. Second, monocytes are associated with inflammation by synthesis of inflammatory molecules following their activation (e.g., after stimulation of Toll-like receptors). Neovascularization is a reparative response to ischemia, and includes 3 processes: angiogenesis, arteriogenesis, and vasculogenesis. Angiogenesis, the formation of new capillary vessels is known to occur in response to a hypoxic environment. The interaction between leukocytes and vascular wall via overexpression of various molecules facilitates the migration of inflammatory cells into the plaque microenvironment. Monocytes are intimately involved in tissue damage and repair and an imbalance of these processes may have detrimental consequences for plaque development and stability. Importantly, monocytes are comprised of distinct subsets with different cell surface markers and functional characteristics and this heterogeneity may be relevant to angiogenic processes in atherosclerosis. The aim of this review article is to present an overview of the available evidence supporting a role for monocytes in angiogenesis and atherosclerosis.

Evaluation of carotid plaque neovascularization using contrast ultrasound.

Contrast-enhanced ultrasound (CEUS) is increasingly used to improve visualization of carotid arteries. However, its reproducibility and utility for clinical research are not well established. The aim of the present study was to assess reproducibility of detection of carotid artery wall neovascularization using CEUS. Complete sequenced CEUS images from 10 individuals were analyzed for the presence of carotid arterial wall neovascularization. The images were acquired using Philips CompactXtreme CX50 ultrasound unit with an L12-3 probe and Bracco SonoVue contrast agent. The carotid wall neovascularization was graded by 2 independent observers with inter-/intraobserver agreement (κ) calculated. Interobserver κ values for intraplaque neovascularization (mean [95% confidence interval]) were 0.67 (0.40-0.94) for the left side. Interobserver κ values for intraplaque neovascularization were 0.65 (0.38-0.92). No study-related complications were observed. The CEUS method although semiquantitative shows moderate-to-strong intra- and interagreement for the results and can be used for clinical research purpose.

Ethnic/racial differences in circulating markers of angiogenesis and their association with cardiovascular risk factors and cardiovascular disease.

OBJECTIVE: To determine (a) whether ethnic/racial differences exist in circulating markers of angiogenesis (Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), soluble Tie-2 receptor (sTie-2) and Angiogenin) between South Asian (SA; from India, Pakistan and Bangladesh); Black African-Caribbean and White (W) ethnic groups, and (b) associations between these markers in stable cardiovascular disease (CVD) and its risk factors. PATIENTS AND METHODS: We recruited 243 subjects (82 SA, 84 Black and 77 W) with symptomatic and clinically confirmed CVD (n=108), risk factor controls (with ≥ 1 cardiovascular risk factor, e.g. smoking, diabetes mellitus, dyslipidaemia, hypertension) and with ankle brachial pressure index >1) (n=64) and healthy controls free of CVD and risk factors (n=56). Angiogenic markers were measured by enzyme linked immunoassay. RESULTS: In healthy controls, angiogenin was higher in SA and Black subjects, compared to Whites (p<0.05). sTie-2 correlated inversely with angiogenin (p=0.001), was higher in women (p=0.029) and was lower in smokers (p=0.007). Overall, age (p=0.001) was the only independent factor associated with angiopoietin-1. Angiogenin (p=0.01) and SBP (p=0.014) were both independently higher in the Black group compared to the White group. CONCLUSIONS: Ethnic, racial, and demographic differences are evident in certain circulating markers of angiogenesis. With the exception of an effect of smoking on sTie-2, these differences are not influenced by the presence of other risk factors, nor the presence of stable cardiovascular disease.

A comparison of the changes in generic quality of life after superficial venous surgery with those after laparoscopic cholecystectomy.

BACKGROUND: Superficial venous surgery (SVS) results in a significant improvement in generic health-related quality of life (HRQL). However, it is unclear how this improvement compares with that observed after other commonly performed general and vascular operations. The aim of this study was to compare the changes in generic HRQL observed before and after SVS for CEAP clinical grade 2 to 4 venous disease with those observed before and after elective laparoscopic cholecystectomy (ELC) for biliary colic. METHODS: The Short Form 12 questionnaire was mailed to patients before and 3, 6, and 12 months after SVS (n = 143) and ELC (n = 60). The responses were used to calculate physical (PCS) and mental (MCS) component summary scores at each time point. A higher score indicates a better HRQL. RESULTS: Before surgery and 3 and 12 months after surgery, patients in the ELC group had a significantly lower PCS than those in the SVS group (40.2 vs 49.5, 48.9 vs 53.1, and 45.4 vs 53.8; P < .001, P = .033, and P < .001, respectively; Mann-Whitney U test). However, the change in PCS observed over the first 12 postoperative months was not significantly different between the SVS and ELC groups. Patients in the ELC group had a significantly lower MCS than those in the SVS group before surgery (45.9 vs 50.8; P = .002; Mann-Whitney U test), but not after surgery. There was no difference between the two groups in terms of postoperative change in MCS. CONCLUSIONS: SVS is associated with a statistically significant and clinically meaningful improvement in generic HRQL that is similar to that observed after ELC. These novel data lend further support to the clinical benefit of SVS and will help health care purchasers make decisions regarding the prioritization of vascular and general surgical services.

Digital venous photoplethysmography in the seated position is a reproducible noninvasive measure of lower limb venous function in patients with isolated superficial venous reflux.

BACKGROUND: The value of photoplethysmography (PPG) has been questioned because of a lack of reproducibility. We performed this study to determine whether new digital technology has improved the reproducibility of PPG in the noninvasive assessment of lower limb venous function in patients with isolated superficial venous reflux. METHODS: This was a prospective study of 140 legs in 110 patients (65% female; median age [interquartile range], 45 years [36-59.25 years]; CEAP clinical grade C2/3, n = 114; C4-6, n = 26) who underwent repeated digital PPG measurements of refilling time (RT) in both the sitting and standing position after standard exercise regimens by a single observer. RT was measured in all patients 2 to 5 minutes apart and in a randomly selected subgroup of 30 patients (38 limbs) 1 to 2 weeks apart. RT variability was assessed by using Bland and Altman's coefficient of repeatability (CR-RT), where the CR-RT was 1.96 times the standard deviation of the mean difference in RT between two tests. Venous duplex scanning of both the deep and superficial veins was also performed, and a reverse flow of greater than 0.5 seconds was considered abnormal. Only patients with isolated superficial venous reflux were included in the study. RESULTS: The CR-RT of the tests on 140 limbs performed 2 to 5 minutes apart was 10 seconds overall, 3 seconds for RT up to 10 seconds, and 16 seconds for RT between 20 and 40 seconds. The CR-RT of the 38 tests performed 1 to 2 weeks apart was also 10 seconds. No systematic variation due to a nonrandom error was found between the measurements performed either 2 to 5 minutes or 1 to 2 weeks apart. CONCLUSIONS: Digital PPG performed in the seated position in patients with isolated superficial venous reflux provides a reproducible method for the noninvasive assessment of lower limb venous function for both clinical and research purposes. However, the variation in precision of RT with the magnitude of the measurement must be taken into account when results are interpreted in individual patients.

Vascular endothelial growth factor and tissue factor in patients with established peripheral artery disease: a link between angiogenesis and thrombogenesis?

Increasing evidence points towards a prothrombotic state in atherosclerosis and its manifestations, such as peripheral artery disease (PAD), which is associated with thrombosis-related complications, such as acute limb ischaemia, graft thrombosis and stroke. We hypothesized that the increased risk of thrombogenesis in PAD may be related to abnormal angiogenesis and, thus, an increased risk of future vascular disease. To test this hypothesis, we measured plasma levels of tissue factor (TF) and related levels to indices of angiogenesis, that is vascular endothelial growth factor (VEGF) and its soluble receptor sFlt-1. We studied 234 patients (145 males; mean age 68.6+/-10 years) with proven PAD (ankle brachial pressure index <0.8) and compared them with 50 healthy controls. Levels of VEGF ( P =0.001) and TF ( P =0.043) were increased in patients compared with controls. There were significant correlations between VEGF and TF levels in both patients (Spearman r =0.351, P <0.001) and healthy controls (Spearman r =0.335, P =0.017). Amongst PAD patients, levels of VEGF were related to gender, with women having higher levels than men. There was no difference in the levels of sFlt-1 between the patients and controls, or between the subgroups of patients. There were however significant correlations between the levels of sFlt-1 and TF (Spearman r =0.268, P <0.001) and between sFlt-1 and VEGF (Spearman r =0.499, P <0.001). In conclusion, patients suffering from proven PAD have higher plasma levels of TF and VEGF compared with controls, with a significant correlation between the two. This suggests a link between the hypercoagulable state in PAD and the process of angiogenesis.

Alterations of thrombogenesis, endothelial damage and oxidative stress with reperfusion during femoral artery bypass surgery for peripheral vascular disease.

Peripheral vascular disease (PVD) is a significant cause of cardiovascular morbidity. We hypothesised that there would be significant alterations of thrombogenesis, platelet activation and endothelial damage, which could be associated with abnormal oxidative stress during femoral artery bypass surgery for PVD, where the femoral artery is cross-clamped (causing acute ischaemia) and reperfused (following revascularisation). To test this hypothesis, we measured sequential changes in von Willebrand factor (vWF, and index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) as well as lipid hydroperoxides (LPO, an index of oxidative stress) in 28 consecutive patients undergoing elective peripheral artery bypass surgery. Mean baseline vWF and sP-sel levels in PVD patients (before clamping) were significantly higher compared with age- and sex-matched controls (unpaired t test, both p < 0.05), but there were no significant differences in TF and LPO levels. There was a correlation between TF and vWF (Spearman's, r = 0.374, p = 0.05), as well as between sP-sel and vWF at the start of surgery (r = 0.467, p = 0.012). The patients undergoing peripheral artery bypass surgery had a mean femoral artery clamp time of 28 min (standard deviation 14 min; range 11-65 min). There were no significant overall changes in sP-sel, vWF, TF and LPO with femoral artery cross-clamping and reperfusion (repeated measures ANOVA, p = NS). In conclusion, we found that during ischaemia-reperfusion during peripheral arterial bypass surgery, thrombogenesis (as measured by plasma TF) and oxidative damage (as measured by LPO) within the affected leg does not increase in the immediate perioperative period. Further studies are required to assess the mechanism(s) of ischaemia-reperfusion injury in PVD, and the contributory role(s) of the endothelium and platelets.

Indices of thrombogenesis, endothelial damage and platelet function following percutaneous peripheral artery angiography and angioplasty for peripheral vascular disease.

We hypothesised that there would be alterations in markers of endothelial damage/dysfunction, platelet activation and thrombogenesis in patients with peripheral vascular disease (PVD) as a result of undergoing diagnostic angiography and therapeutic angioplasty. To test this hypothesis, we measured sequential changes in von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) in 52 consecutive patients (32 male; mean age 69 years, SD 10) who were undergoing elective angiography and angioplasty for PVD. Patients with PVD had significantly higher vWf and sP-sel levels compared to healthy controls (both p < 0.001), but median TF levels were not significantly different (p = 0.344). In the whole group, there was a significant reduction in sP-sel levels (p < 0.001, paired t test) post-angiography/angioplasty, but no significant change in vWf and TF levels. In patients undergoing angiography only, there was a significant drop in mean sP-sel (p < 0.001, paired t test) and vWf (p = 0.044) values after the procedure, whilst TF levels were not significantly changed (p = 0.370, Mann-Whitney U test). In patients undergoing angioplasty and stent, mean sP-sel levels fell immediately after the procedure (p = 0.001, paired t test), but there were no statistically significant changes in vWf and TF-levels. In conclusion, there appears to be a reduction in plasma sP-sel levels following angioplasty and stenting for PVD, suggesting alterations in platelet physiology, which may be accompanied by some alterations in the endothelium. The possibility that these changes may have pathophysiological implications for understanding platelet and endothelial reactions to angiography and associated interventions (that is, angioplasty and stent) needs to be explored.

Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Relationship with von Willebrand factor and tissue factor.

BACKGROUND: Increased numbers of CD146-defined circulating endothelial cells (CECs), as are present in the peripheral blood of patients suffering acute coronary syndromes, imply injury to the endothelium. Endothelial damage can also be assessed by the measurement of plasma levels of von Willebrand factor (vWf). Increased levels of procoagulant plasma tissue factor (TF), arising from monocytes/macrophages and endothelial cells, is present in atherosclerosis. We hypothesised increased CECs in patients with ischaemic rest pain (IRP) of the lower limb due to peripheral atherosclerosis and comparable to that seen in patients with acute myocardial infarction (AMI), when compared to patients with intermittent claudication (IC) or healthy controls that would correlate with vWf and TF. PATIENTS AND METHODS: We recruited 20 patients in each of four groups: (i) IRP of the lower limb; (ii) AMI; (iii) 'stable' IC; and (iv) healthy controls. CD146-expressing CECs were measured by immumomagnetic separation and counting under a fluorescence microscope; plasma vWf and TF by ELISA. RESULTS: In IRP, median (IQR) CEC levels were 3.5 (2.0-5.8) cells/ml, in IC were 1.1 (0.6-2.9) cells/ml, and in healthy controls were 1.0 (0.5-1.7) cells/ml (p<0.001). The levels of vWf (p=0.034) and TF (p=0.007) were also significantly different between the groups, with the highest levels in patients with IRP. Levels of CECs correlated with vWf (rs=0.4, p=0.002) and TF ( rs=0.296, p=0.021 ). In AMI, CEC levels were higher than those in IRP at 4.9 (3.6-8.4) cells/ml (p=0.0385). CONCLUSION: This study demonstrates evidence of direct endothelial cell injury (i.e. raised CECs) in patients with IRP that correlated with vWf and TF, but that this is less severe than in AMI.

Vascular endothelial growth factor and its receptor, Flt-1, in the plasma of patients with coronary or peripheral atherosclerosis, or Type II diabetes.

Since atherosclerosis is characterized by endothelial damage, re-growth seems likely to be occurring in order to repair or replace injured cells. Angiogenic vascular endothelial growth factor (VEGF), a likely mediator of these events, acts on the endothelium via a specific receptor, Flt-1. We hypothesized that patients with different manifestations of atherosclerosis, and others with diabetes, would have altered plasma levels of VEGF and Flt-1 compared with healthy individuals. Accordingly, 70 patients with peripheral artery disease (PAD), 70 patients with coronary artery disease (CAD), and 70 age- and sex-matched healthy controls were recruited. We also recruited 14 patients with diabetes asymptomatic for atherosclerosis, 14 patients with diabetes and atherosclerosis, and 14 age- and sex-matched controls. VEGF and soluble Flt-1 (sFlt-1) were measured by ELISA. In the main study of PAD and CAD, VEGF was raised in both patient groups (P<0.05) compared with the controls, but was not different between the patient groups. sFlt-1 was lower in patients with PAD (P<0.05), but not in those with CAD, compared with the controls. VEGF was raised in the patients with diabetes plus atherosclerosis (P<0.05), but not in the group with diabetes alone; levels of sFlt-1 were unaltered in both diabetes groups. Our data point to changes in plasma levels of VEGF and its receptor sFlt-1 in diabetes and atherosclerosis that may have relevance for therapy and angiogenesis in these conditions.

The prevalence of hyperhomocysteinemia, methylene tetrahydrofolate reductase C677T mutation, and vitamin B12 and folate deficiency in patients with chronic venous insufficiency.

INTRODUCTION: Hyperhomocysteinemia (HHcy) is a risk factor for venous thromboembolism, which in turn is a major cause of chronic venous insufficiency. HHcy may be more common in patients with chronic venous insufficiency, but the cause is unknown. METHODS: One hundred hospital outpatients (52 women; median age, 66.5 years [interquartile range, 53-77 years] with venous disease C(2-6) underwent assessment of serum vitamin B(12) and folate concentration, plasma Hcy concentration, and C677T methylene tetrahydrofolate reductase (MTHR) homozygosity with polymerase chain reaction. HHcy was defined as greater than 15 micromol/L, the 95th centile of the normal range. RESULTS: CEAP classification was C(2) in 39 patients, C(3) in 10 patients, C(4) in 13 patients, C(5) in 15 patients, and C(6) in 23 patients, with median Hcy concentration 11.6, 11.5, 12.5, 15.1, and 18.1 micromol/L, respectively (Kruskall-Wallis test, P <.001). Overall prevalence of HHcy was 39% (P <.001, binomial test vs normal population), and was significantly related (Pearson chi(2) for trend, 13.616; P <.009) to clinical grade: C(2), 23%; C(3), 20%; C(4), 39%; C(5), 53%; C(6), 65%. In a linear regression model, C(6) disease was a strong independent predictor (R(2) = 20.1%) for Hcy. Overall, 5 of 49 patients (10%, NS compared with normal population [5%]) with C(2-3) disease and 10 of 51 patients (20%) (P <.001, binomial test) with C(4-6) disease were homozygous for the C677T MTHFR polymorphism. Hcy levels and prevalence of HHcy were negatively correlated with vitamin B(12) levels (r = -0.248, P =.021, and r = -0.225;, P =.037, respectively). There was no significant relationship with folate. HHcy was present in 3 patients (all with C(5-6) disease) with either vitamin B(12) or folate deficiency, and in 8 of 15 patients homozygous for MTHFR C677T. No patient had HHcy, vitamin deficiency, and C677T mutation. CONCLUSION: HHcy is common in patients with chronic venous insufficiency, especially those with ulceration. However, inasmuch as fewer than a third of patients with HHcy were C677T MTHFR homozygous or had vitamin B(12) or folate deficiency, other mechanisms must be responsible in the majority. Further work is required to determine the cause of HHcy in chronic venous insufficiency, whether HHcy is causally related to development and progression of the disease, and whether treatment would be beneficial.