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Objectives: To determine if cardiovascular disease may be a risk factor in the development of chronic idiopathic axonal polyneuropathy (CIAP). Methods: In this incidence case-control study, the prevalence of cardiovascular disease and risk factors in 97 patients with CIAP (mean age 67.5 (SD 7.9) years) and the prevalence of neuropathic features in 97 patients with peripheral arterial disease (PAD) (mean age 67.1 (SD 7.3) years) were investigated. The results were compared with those for 96 age and sex matched controls without diagnosed PAD or polyneuropathy (mean age 67.5 (SD 9.1) years). In a randomly chosen subgroup of 23 patients with CIAP, 42 patients with PAD, and 48 controls, an electrodiagnostic investigation was performed. Results: Patients with CIAP more often had manifest cardiovascular disease and cardiovascular risk factors than controls (stroke 18% v 6% of patients, odds ratio (OR) 3.2 (95% confidence interval (CI) 1.8 to 5.9); heart disease 29% v 15%, OR 2.4 (95% CI 1.2 to 4.9); family history of cardiovascular disease 42% v 21%, OR 2.8 (95% CI (1.5 to 5.2); hypertension 56% v 39%, OR 2.0 (95% CI 1.1 to 3.6); hypercholesterolaemia 46% v 21%, OR 3.3 (95% CI 1.5 to 7.3); current smoking 38% v 23%, OR 2.1 (95% CI 1.1 to 3.9)). The prevalence of cardiovascular disease and cardiovascular risk factors was lower than in patients with PAD. Patients with PAD more often had polyneuropathy than controls (15% v 5%, OR 3.3 (95% CI 1.1 to 10.0)). There was a trend towards lower nerve conduction velocities and lower amplitudes on electrodiagnostic investigation compared with controls. Conclusion: This study shows that cardiovascular disease and CIAP often coexist, and therefore cardiovascular disease may be a cofactor in the development of CIAP.

For chronic idiopathic axonal polyneuropathy (CIAP), even after extensive evaluation, no cause has yet been found. Considering the age and sex distribution of patients with this disease, it is possible that vascular disease plays a role in the development of this polyneuropathy. As endoneurial vessel abnormalities can be related to ischemia, we investigated endoneurial vessels in sural nerve biopsies of 18 patients with CIAP. As controls we used sural nerves of 4 patients with diabetes mellitus, 6 patients with hereditary motor and sensory neuropathy type II (HMSN type III) and 10 autopsy cases. Basal lamina area thickness, endothelial cell area, lumen area, and the number of basal laminae, endothelial cells and periendothelial cell nuclei were investigated. Basal lamina area thickness, endoneurial cell area and number of endothelial cell nuclei in CIAP were increased in comparison with HMSN type III, whereas the basal lamina area thickness of patients with CIAP and diabetes mellitus were in the same range. The structure of the basal lamina area in CIAP differed from diabetes mellitus; in diabetes mellitus there was a larger number of lamellae, whereas in CIAP there was an increase in collagen. There was no correlation between basal lamina area thickness and age. In CIAP patients with peripheral vascular disease of the legs, basal lamina area thickness was increased. The relation between basal lamina area thickening and peripheral vascular disease of the legs in CIAP may indicate a role for ischemia in the development of this polyneuropathy.

SummaryBackground: Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation.Methods: Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens.Results: Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively.Conclusions: A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

In a prospective double-blind trial, we treated 194 patients with acute venous thromboembolism with heparin or low molecular weight heparin (LMWH; Fragmin). To evaluate the most important prognostic factors for bleeding, the presenting clinical features of the patients, the patients' anticoagulant responses, and the doses of the drugs were analyzed using univariate and multivariate regression analyses. No significant differences in clinical risk factors associated with bleeding were observed between heparin and LMWH. The univariate analyses ranked the parameters in the following order of importance: World Health Organization (WHO) performance status, history of bleeding tendency, cardiopulmonary resuscitation, recent trauma or surgery, leukocyte counts, platelet counts, duration of symptoms, and body surface area. Patients with WHO grade 4 had an eightfold increase in risk of bleeding as compared with WHO grade 1. Assessment of the individual contribution of each variable using multivariate regression analysis showed that the WHO performance status was the most important independent factor predicting major bleeding. A history of a bleeding tendency, recent trauma or surgery, and body surface area were also independent risk factors. The risk of bleeding was influenced by two factors related to the treatment, the patient's anticoagulant response as measured with the anti-Xa assay and the dose of the drug expressed as U/24 h/m2. An increased risk of bleeding was only observed at mean anti-Xa levels greater than 0.8 U/mL for both drugs. Significantly more major bleedings occurred in patients treated with high doses of the drugs, an observation that was independent of the concomitant anti-Xa levels. It should be considered whether choosing an appropriate initial dose adapted to the patient's body surface area and clinical risk factors can improve the efficacy to safety ratio of heparin treatment.

The term 'neurovascular compression syndrome' refers to a heterogeneous group of signs and symptoms thought to be generated by the compression of arteries, veins or nerves, which is caused by the anatomical relationships of muscles, ligaments and bony structures in the thoracic outlet. Most cases are related to nerve compression; arterial and venous compression accounts for 1-3% of cases. The term 'neurovascular compression syndrome', which does not refer to a single entity, is confusing and should be avoided. Rather, a clinical problem thought to arise in the thoracic outlet should be described in terms of the underlying arterial, venous or nerve impairment. Indications for surgical intervention are limited: there is no evidence to suggest that patients who undergo surgery fare better than those who receive non-surgical treatment.

Angina pectoris (letterlijk: pijn op de borst, in engere zin, pijn ten gevolge van ischemie in het myocard) is meestal zo duidelijk dat het wordt herkend. Er is een duidelijk patroon van pijn op de borst, uitgelokt door inspanning, blootstelling aan koude, na een zware maaltijd of bij emotie. In een minderheid van de gevallen ontbreekt dit klassieke patroon en is er zelfs na herhaalde anamnese en aanvullend onderzoek nog aanzienlijke twijfel over de oorzaak van de pijn.

The Dutch national guidelines for the diagnosis of patients with clinically suspected pulmonary embolism (from 1992 en 1998) are poorly followed in clinical practice, due especially to practical objections. A large multicentre trial to investigate the diagnostic accuracy of the available modalities and of recently developed techniques such as D-dimer determination, (99m)Tc-gas-scintigraphy and spiral CT scanning was started in I997. In the first phase, the diagnostic value was assessed of: spiral CT (sensitivity 69%, specificity 84%; sensitivity for segmental and larger pulmonary embolisms (PE) 86% and for subsegmental PE 21%), (99m)Tc-gas-ventilation scintigraphy (no improvement compared to conventional ventilation scintigraphy), D-dimer determination (sensitivity for segmental PE 93% and for subsegmental PE 53%, specificity 63%), clinical decision rules (in combination with D-dimer determination; sensitivity 100%, specificity 11%) and echography of the deep venous system (sensitivity 26% for segmental PE and 7% for subsegmental PE, specificity 97%). In the second phase, the feasibility of two new potentially cost-effective diagnostic algorithms was evaluated on the basis of the results obtained in the first phase and data in the literature. In 631 patients, a clinical risk estimate was made and D-dimer determination was done, followed by a ventilation-perfusion scan and serial compression echography of the leg veins. An apparent recurrence of PE occurred in 6 of 466 patients in whom no PE had been found originally (1.3%; 95% CI: 0.5-2.8). The average costs were 812 Euro,--per patient. In 510 patients, a spiral CT followed by compression echography was performed. Recurrent PE occurred in 3 of 378 patients with initial normal tests (0.8%; 95% CI: 0.2-2.3). The average costs were 883 Euro,--per patient. A combination of both strategies can be cost-effective with a cost 674 Euro,--per patient (recurrence rate: 1.9%). Both the strategy starting with a clinical-risk estimate and a D-dimer determination as well as the strategy consisting of spiral CT and serial echography were safe and cost-effective. According to the results of a survey of hospital directors, internists and pulmonologists, both are well accepted in clinical practice.

Large-scale trials have shown that primary prevention using acetylsalicylic acid is useful in all patients with a cardiovascular risk exceeding 1.5% annually. In these patients the benefits of prevention outweigh the risks of bleeding. Almost all patients with diabetes mellitus are at high risk of developing cardiovascular disease. Additionally, most diabetics have other cardiovascular risks besides diabetes, providing further argument for prevention with acetylsalicylic acid. Only very few prospective trials have confirmed that acetylsalicylic acid treatment in patients with diabetes mellitus reduces their risk of cardiovascular disease and myocardial infarction. Treatment with acetylsalicylic acid should be considered in all patients with diabetes, especially in view of their decreased survival after a cardiovascular event, myocardial infarction in particular. If acetylsalicylic acid is contra-indicated treatment with clopidogrel is an alternative.

Tracing and treating cardiovascular risk factors in patients with arterial vascular disease and in patients with high risk of developing vascular diseases.Descriptive.In September 1996 at the University Medical Center Utrecht, the Netherlands, a vascular screening and prevention programme was started for newly referred patients aged between 18 and 79 years presenting with one or more of the following: coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, diabetes mellitus or lipid disorders. In all patients, risk factors for developing (new) vascular diseases were assessed and non-invasive vascular diagnostics aimed at finding asymptomatic vascular disease were done.Between 1 September 1996 and 31 October 2002, 3075 patients took part in the screening programme. Within the various patient groups and often despite treatment, there was a high prevalence of hypertension, smoking, dyslipidaemia, hyperhomocystemia and overweight. In patients with peripheral artery disease, carotid artery stenosisor = 50% was detected in 17% and an aneurysm of the abdominal aorta in 5%. In patients presenting with diabetes mellitus, hypertension or lipid disorders the prevalence of asymptomatic arterial disease was 1-5%. Asymptomatic vaso-dilatory disease in particular was uncommon.A hospital-wide vascular screening and prevention programme for a wide range of high-risk vascular patients was shown to be feasible and resulted in the detection of risk factors and asymptomatic arterial disease. It is a reliable starting point for actual risk intervention. More attention should be paid to treating existing risk factors.

Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might be an effective method to improve endothelial function in these patients.A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 mg and 80 mg on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease.Patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite substantial lowering of all atherogenic lipid parameters, no improvement of endothelium-dependent vasodilatation was found (P0.8).We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.

Elevated serum levels of homocysteine are considered a risk factor for cardiovascular disease. It has been suggested that homocysteine is a late stage predictor of adverse cardiovascular events, which might explain reported controversies in literature. The objective of the present study was to study the relationship between homocysteine levels and the stage of atherosclerotic disease.In a cross-sectional study we compared the prevalence of hyperhomocysteinemia in high risk patients without silent or clinically overt atherosclerosis (group I, n = 196) with two patient groups: patients with clinically manifest atherosclerosis in the past or asymptomatic atherosclerosis (group II, n = 364) and patients who currently suffer from a clinically relevant manifestation of ischemic cardiovascular disease (group III, n = 967). In addition, we related homocysteine levels with a cumulative index of atherosclerotic disease (SMART-score).Homocysteine levels (micromol L(-1)) for the different groups were 13.5 +/- 8.9 (group I), 13.7 +/- 8.2 (group II) and 14.7 +/- 7.7 (group III). After adjustment for age, body mass index, creatinine levels and current use of vitamins, no significant differences in the prevalence of hyperhomocysteinemia were observed, compared with the reference category. Linear regression analysis revealed a significant relationship between Smart score and homocysteine levels that remained after adjustment for potential confounders (Beta = 0.36 (0.14-0.59), P = 0.001).If homocysteine levels are associated with the presence and indicators of atherosclerotic plaque burden, then this relationship is apparently not affected by the stage of atherosclerotic disease.

Rhabdomyolysis is a rare but potentially fatal complication associated with the use of cholesterol synthesis inhibitors (statins). The complication can develop in susceptible patients and with the concomitant use of medications that impede the biodegradation of statins, for example, biotransformation via the cytochrome P450 system. This may result in the plasma and tissue concentrations of statins, and their active metabolites, increasing to levels that are toxic for striated muscle. Myopathy is present when plasma activity levels of creatinine kinase are raised to in excess of 10 times the upper limit of the normal value. Muscular complaints which may be indicative of myotoxicity and subsequent myopathy are present in 1-7% of statin users. Albeit to varying degrees, all statins can induce myotoxicity especially at high dosages. Rhabdomyolysis was clearly more prevalent under cerivastatin users than the users of other statins and was therefore recently withdrawn from the market. Statins should be withdrawn immediately if myopathy is suspected. Prompt withdrawal may prevent rhabdomyolysis.

To compare the effects of 3 months treatment with tibolone (a single entity synthetic steroid hormone with estrogenic, progestanic and androgenic activities), or continuous combined conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA), with placebo, on endothelial function.A single center, randomized, double-blind, placebo-controlled study.Research center as part of the University Medical Center Utrecht.One hundred and five healthy postmenopausal women, sampled from the general population.Three months treatment with tibolone or CEE+MPA or placebo.At baseline and after 3 months, endothelial function was assessed non-invasively by measuring percent lumen diameter change in the brachial artery after reactive hyperemia and sublingual nitroglycerine spray.Results are presented as mean differences between treatment groups of endothelium dependent flow mediated dilatation (fmd) and endothelium independent nitroglycerine induced dilatation with 95% confidence intervals (95% CI). After treatment, there was a significant difference in mean fmd between the CEE+MPA group and the placebo group of 2.5% (95% CI: 0.3-4.6) while the tibolone group and the placebo group did not differ significantly (0.6%; 95% CI: 1.6-2.8). Nitroglycerine induced dilatation did not differ significantly between the groups.Hormone replacement therapy with CEE+MPA for 3 months increases endothelium dependent fmd of the brachial artery in healthy postmenopausal women. Tibolone did not alter fmd. The clinical significance of this improvement in fmd for cardiovascular disease risk needs to be established.

Patients with diabetes mellitus are at high risk of cardiovascular diseases. Dyslipidemia is an important risk factor for cardiovascular complications in diabetes. Increased triglyceride and reduced HDL-cholesterol plasma concentrations are common features of dyslipidemia in type 2 diabetes. The LDL particles are small and dense and have an increased atherogenity. Abnormalities in lipoprotein composition are observed in diabetes mellitus, especially in type 2. Post-hoc subgroup analyses of studies on the effect of lipid-lowering therapy on cardiovascular events suggest that treatment of dyslipidemia in diabetes may prevent cardiovascular complications. There are increasing indications that dyslipidemia in diabetes mellitus deserves aggressive treatment and that lipid target levels should be very low.

We evaluated selection bias in a prospective study of 1,162 consecutive patients with suspected pulmonary embolism. Of these, 983 were eligible, and 627 could actually be included. During two months extensive data were collected on all non-included patients. Finally, our patient characteristics were compared with those of the PIOPED study (1990) and the study of Hull et al. (1994). Compared with included patients, the non-included patients had more often non-diagnostic V/Q scans (50% vs. 36%, p0.01) and were more often already hospitalized (31% vs. 22%, P = 0.04). The subgroup of patients not included due to refusal or inability to give informed consent (IC) was older (mean age 61 vs. 53 years, P0.01), more often suffered from malignancies (26% vs. 11%, P0.01) and frequently had non-diagnostic V/Q scans (57%) as compared to included patients. In our study, 54% of all patients screened was eventually included versus 27% in the PIOPED study. In the PIOPED study patients who had contra-indications for pulmonary angiography were excluded, while in the study of Hull et al. those with inadequate cardiorespiratory reserve were excluded. In studies on new diagnostic technologies, patient selection bias does occur. The potential for such a selection bias should be taken into account when diagnostic strategies are devised to improve their generalizability and acceptability.

Platelet adhesion to collagen is the initial step in both hemostasis and thrombosis; this adhesion is mediated by alpha(2)beta(1) on the surface of platelet membranes. An 807 C to T single nucleotide exchange polymorphism close to the gene coding for the alpha(2) subunit of alpha(2)beta(1) is associated with the density of alpha(2)beta(1) on the platelet membrane.We studied the relation of the alpha(2)beta(1) 807 C/T genotype to cardiovascular mortality in a prospective cohort study of 12 239 women who were invited for the breast cancer screening program of Utrecht, the Netherlands. The initial age was between 52 and 67 years. Women were followed on vital status between 1976 and 1995 (168 513 women-years). Data were analyzed by using a nested case-control design. The alpha(2)beta(1) 807 C/T genotype was not associated with cardiovascular mortality in the total population: the rate ratio for cardiovascular mortality in 807 TT homozygotes compared with 807 CC wild types was 1.2 (95% CI 0.8 to 1.7). However, the alpha(2)beta(1) 807 T polymorphism was associated with an increased risk of cardiovascular mortality in women who smoked or in women who had indications of compromised endothelium, such as diabetes and microalbuminuria. In those who were exposed to/=2 of these factors, the risk ratio (95% CI) between alpha(2)beta(1) 807 TT homozygotes and 807 CC wild types was 14.1 (5.0 to 39.9).alpha(2)beta(1) 807 TT homozygosity, coding for increased alpha(2)beta(1) density on the platelet membrane, is associated with an increased risk of cardiovascular mortality in those women with indications of compromised endothelium.

To determine the prevalence of hypercholesterolaemia and the use of lipid-lowering medication in patients with a manifest vascular disease.Prospective, cross-sectional.In patients who visited the University Medical Centre Utrecht, the Netherlands, for the first time with a manifestation of atherosclerosis in the period 1 September 1996-15 November 1998, we determined by a single measurement of the cholesterol if they were eligible for lipid-lowering medication according to the cholesterol cut-off value mentioned in the new Dutch cholesterol guidelines (1998) of the Dutch Institute for Health Care Improvement.The study group comprised 737 patients: 539 (73%) males and 198 (27%) females, with a mean age of 62 year. 500 (68%) were eligible for lipid-lowering treatment. 66 patients (9%) were being treated according to the guidelines and in 106 (14%) the aim of a cholesterol lower than 5.0 mmol/1 was not reached despite cholesterol lowering medication. In 328 patients (45%) hyperlipidaemia was not treated pharmacologically.Two-thirds of the patients with manifest vascular disease had hypercholesterolaemia. Many of these patients were not yet being treated.

Therapeutic angiogenesis by injection of growth factors or genes encoding for these appears a promising strategy for treatment of critical limb ischaemia but is currently still in an experimental phase. Among the cytokines that promote angiogenesis, i.e. the postnatal growth of blood vessels due to activation and proliferation of endothelial cells, vascular endothelial growth factor (VEGF) takes a special position. VEGF has proven to be a powerful angiogenic factor in vivo that specifically promotes migration and replication of endothelial cells. The specificity of VEGF for endothelial cells, compared with the more widespread effects of other factors such as fibroblast growth factor (FGF), may provide a broader therapeutic potential. The recombinant form of the human VEGF gene can be injected intramuscularly as a plasmid (phVEGF). The angiogenic effect of phVEGF can be explained in several ways: by direct stimulation of proliferation and migration of endothelial cells in vivo; by recruitment of previously existing collaterals; and by improving vasomotor function of vessels in ischaemic tissue.

Evidence is emerging that the contribution of atherosclerosis to the development of abdominal aortic aneurysm may differ from that of other manifestations of arterial disease. B-mode ultrasound may be helpful in understanding the characteristics and factors that contribute to the development of different manifestations of arterial disease. We examined whether there is a difference in common carotid intima-media thickness (IMT), an indicator of generalized atherosclerosis, in patients with peripheral arterial disease (PAD) and abdominal aortic aneurysm (AAA). IMT of the left and right common carotid artery was measured in the first 172 patients (123 PAD and 49 AAA) enrolled in the Second Manifestations of ARTerial disease (SMART) study, a cohort study among patients with a manifestation of atherosclerotic vascular disease or risk factors for atherosclerosis. Mean IMT was 0.98 +/- 0.34 mm in patients with PAD and 0.91 +/- 0.20 mm in patients with AAA, with an age and sex adjusted mean difference of 0.18 mm (95% CI 0.08; 0.28). After additional adjustments for cardiovascular risk factors, the difference remained 0.11 mm (95% Cl 0.01; 0.21). Common carotid IMT in patients with AAA is on average smaller than in patients with PAD, independent of other determinants of IMT. These findings support the view that the development of AAA cannot completely be explained by atherosclerosis and is in part due to other pathophysiological mechanisms.

Objective. To identify the optimal dose of oral iloprost bn the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. Design. Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. Setting. European university hospitals. Patients. A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. Intervention. Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 mu g or oral iloprost 100 mu g. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 mu g. Measurements. The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. Results. A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 mu g and 35 received iloprost 100 mu g. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment:differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 mu g and 64% iloprost 100 mu g (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 mu g and 97% on oral iloprost 100 mu g. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. Conclusion. The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 mu g oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 mu g iloprost dose was better tolerated in this patient group.

To assess current practice in screening for asymptomatic vascular disease and risk factors in patients referred with vascular disease or cardiovascular risk factors.Descriptive, retrospective.University Hospital Utrecht, Utrecht, the Netherlands.By means of the computerized hospital registration system all patients who were referred to the outpatient clinic with carotid stenosis, peripheral artery disease, abdominal aortic aneurysm, diabetes mellitus, hyperlipidaemia or hypertension during one year were identified. By means of the same hospital registration system the frequency of diagnostic tests performed to detect atherosclerosis or risk factors in these patients within a period of 5 months round the first attendance was determined.372 Patients with a vascular disease and 317 patients with a risk factor were identified. Tests to detect carotid stenosis, peripheral artery disease or an abdominal aortic aneurysm were each performed in less then 6% of all patients except the test for abdominal aortic aneurysm. Tests to detect coronary artery disease were performed in about 50% of all patients. Tests to detect diabetes mellitus were performed in 35% of the patients with vascular disease and in 81% of the patients presenting with hyperlipidaemia or hypertension. Tests to detect hyperlipidaemia were performed in 18% of the patients with a vascular disease and in 76% of the patients with diabetes or hypertension.The results of this study suggest that in current practice patients referred for vascular disease or cardiovascular risk factors are infrequently screened for asymptomatic macrovascular disease and risk factors.

Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation.Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens.Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively.A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.

The effects of pneumoperitoneum on peak venous flow velocity in the common femoral vein and the vena cava have already been studied. The results suggested that venous stasis occurs during surgical pneumoperitoneum. This study determines the effects of pneumoperitoneum on the overall venous outflow resistance of the lower limbs. Venous outflow resistance was measured during surgical procedures by impedance plethysmography in 12 patients undergoing laparoscopic cholecystectomy, 4 patients undergoing laparoscopic herniorrhaphy, 4 patients undergoing conventional cholecystectomy, and 2 patients undergoing conventional herniorrhaphy. Venous outflow resistance did not change significantly during laparoscopic cholecystectomy or herniorrhaphy. No difference in venous outflow resistance between laparoscopic cholecystectomy and herniorrhaphy was found. During pneumoperitoneum, no obstruction to total lower limb venous outflow could be demonstrated, indicating that venous stasis in the limbs did not occur, and consequently, flow in the iliac and inferior caval veins was not compromised. Hypothetically, active vasodilatation resulting from mild compression may explain this. In our view, no special measures to prevent deep venous thrombosis have to be taken during laparoscopic procedures.

Breast arterial calcification (BAC) has been associated with diabetes and hypertension. This prompted the authors to study the relation between BAC and cardiovascular mortality in a cohort of 12,239 women aged 50-68 years who participated in a population-based breast cancer screening project (DOM Project) in Utrecht, the Netherlands, during the period 1975-1977. Mortality data from 16-19 years of follow-up were available. The occurrence of outcome events was compared in terms of hazard ratios. Cardiovascular risk factors, including age, diabetes mellitus, hypertension, parity, Quetelet index, and smoking, were studied to identify possible confounders. Arterial calcification was seen in 9% of the women. The hazard ratio for overall mortality was 1.29 (95% confidence interval 1.06-1.58) in women with BAC detected on screening mammograms in comparison with women without BAC after correction for the above-mentioned factors. An excess of all-cause mortality was found in diabetic women with BAC (hazard ratio = 1.74, 95% confidence interval 1.19-2.56), which was also present in subgroups of coronary mortality. These results indicate that BAC is associated with an increased risk of subsequent cardiovascular death in women over age 50 years and in diabetic women in particular.

Plasminogen activation by tissue–plasminogen activator (t-PA) is accelerated by the presence of a macromolecular surface, which acts as a template that brings enzyme and substrate in close proximity. Modification of lysine residues, which are important for this template function, occurs in diabetic patients as a consequence of glycation of proteins. In this study, we investigated the effects of glycation of fibrin and other proteins in t-PA-catalyzed plasmin formation. Plasminogen activation on glycated fibrin(ogen) was increased compared to non-glycated fibrin(ogen), which could fully be attributed to an increased affinity of t-PA for glycated fibrin(ogen). Binding of plasminogen to glycated fibrin was increased, but did not contribute to increased plasminogen activation. Both plasminogen activator inhibitor-1 (PAI-1) binding and activity were increased on glycated fibrin. Induction of template function in plasminogen activation was also observed on immobilized glycated bovine serum albumin (BSA) and human γ-globulins (IgG). Increased plasmin generation at sites of deposition of glycated proteins may lead to increased extracellular matrix breakdown and thereby affect the integrity of the endothelial monolayer. Moreover, soluble glycated BSA and glycated IgG can inhibit t-PA binding to immobilized glycated fibrin and interfere with fibrinolysis in diabetic patients.

Glycation of proteins of the vessel wall is thought to play an important role in the pathogenesis of vascular complications in diabetes by affecting structure and function of these proteins. Adhesive proteins in the extracellular matrix (ECM) of endothelial cells (ECs) are essential for attachment of ECs to the subintima. In this study, we investigated the effect of glycation of ECM and purified adhesive proteins on EC adhesion and spreading. ECM was incubated with the reactive sugar glucose-6-phosphate (0–500 mmol/l) for different time periods (0–14 days) at 37°C. Degree of glycation, measured in an enzyme-linked immunosorbent assay using a monoclonal antibody specific for advanced glycation end products, increased in a timeand concentration-dependent manner. Glycation of ECM with 50 mmol/l glucose-6-phosphate resulted in increased coverage by ECs as measured in a cell adhesion assay and was the result of an increase in number of adhered cells, while cell size was unaffected. Glycation of ECM with higher concentrations of glucose-6-phosphate resulted in decreased coverage by ECs caused by both a reduction in number of adhered ECs and impaired spreading. Experiments with purified glycated matrix proteins indicate that the decrease in EC adhesion and spreading on glycated ECM may result from glycation of vitronectin. Impaired EC adhesion and spreading caused by vitronectin glycation may result in impaired endothelial function and contribute to vascular disease.

Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism.Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial.One university and 2 regional teaching hospitals.188 patients treated with heparin or danaparoid for acute venous thromboembolism.The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively.Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface areaor = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders.A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Aims The metabolic syndrome is associated with an increased risk of cardiovascular disease in patients without a cardiovascular history. We investigated whether the metabolic syndrome is related to the extent of vascular damage in patients with various manifestations of vascular disease. Methods and results The study population of this cross-sectional survey consisted of 502 patients recently diagnosed with coronary heart disease (CHD), 236 with stroke, 218 with peripheral arterial disease (PAD) and 89 with abdominal aortic aneurysm (AAA). Metabolic syndrome was diagnosed according to Adult Treatment Panel III criteria. Carotid Intima Media Thickness (IMT), Ankle Brachial Pressure Index (ABPI) and albuminuria were used as non-invasive markers of vascular damage and adjusted for age and sex if appropriate. The prevalence of the metabolic syndrome in the study population was 45%. In PAD patients this was 57%; in CHD patients 40%, in stroke patients 43% and in AAA patients 45%. Patients with the metabolic syndrome had an increased mean IMT (0.98 vs 0.92 mm, P-value

Fluvastatin monotherapy up to 40 mg/day over 52 weeks in patients with primary hypercholesterolemia decreased plasma low density lipoprotein cholesterol (LDL-C) by 28%, with varying decreases in plasma triglycerides and increases in high density lipoprotein cholesterol (HDL-C). Patients completing the 52-week study participated in a further trial to assess whether the efficacy of fluvastatin (20-40 mg/day), either as monotherapy or in combination with cholestyramine (CME; 4-16 g/day), taken at least 4 hours prior to fluvastatin, is sustained for up to 3 years. Patients were assessed every 12 weeks on average for safety and efficacy, the latter being calculated as a percent change from baseline of lipids or lipoproteins. During the second year (endpoint up to week 104), 147 patients received monotherapy (estimated mean dose, 30.2 mg/day) and 127 received additional CME (38.1 mg/day fluvastatin plus 10.1 g/day CME). During the third year (endpoint up to week 156), 140 patients received monotherapy (32.5 mg/day) and 67 received additional CME (39.3 mg/day fluvastatin plus 10.3 mg/day CME). Statistically significant reductions in mean total cholesterol and LDL-C and increases in mean HDL-C were achieved in both treatment groups and maintained throughout the study. A significant reduction in triglyceride levels was only observed at the second year endpoint in patients receiving monotherapy (-10.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

In this long-term (52-week) open-label extension to an earlier randomized, multicenter, double-blind, placebo-controlled, dose-finding trial, 381 patients with primary hypercholesterolemia received fluvastatin at increasing doses of 10 to 40 mg/day to achieve plasma low-density lipoprotein (LDL) cholesterol normalization, according to the European Atherosclerosis Society guidelines. The aim of the extension study was to assess the long-term efficacy, safety, and tolerability of fluvastatin. After 52 weeks of therapy, 75% of patients were receiving fluvastatin at 40 mg/day (mean dose: 36 +/- 8 mg/day). The mean percent change in LDL-cholesterol levels from baseline was -24.8% (p0.001), and 82.6% of patients achieved an LDL-cholesterol reduction ofor = 15%. In patients in the lowest baseline quintile, high-density lipoprotein-cholesterol levels were significantly (p0.001) increased by 8.8% whereas, in the highest baseline quintile, triglycerides were significantly (p0.001) reduced by 15.3%. Plasma lipoparticle (a) [Lp(a)]:B levels were also significantly reduced (-38.6%; p0.001). Fluvastatin was considered to be well tolerated by the majority of patients by both patients and investigators. The most frequently reported adverse event was abdominal pain. Notable biochemical abnormalities were rare. In conclusion, the results of this extension study indicate that fluvastatin at dosages of 20-40 mg/day is effective and well tolerated in patients with primary hypercholesterolemia and is accompanied by no particular problems of safety.

OBJECTIVE To assess the effects of low-dose eicosapentaenoic acid-ethyl-ester on diabetes regulation, lipid metabolism, blood rheology, and platelet reactivity. RESEARCH DESIGN AND METHODS In a double-blind, randomized, placebo-controlled study, 24 NIDDM subjects received 1800 mg of EPA-E, 900 mg of EPA-E, or a placebo (1656 mg olive oil) daily for 8 wk. RESULTS The EPA: arachidonic acid plasma ratio increased over an 8-wk period, then declined after a 4-wk wash-out period in the fish-oil groups in a dosedependent way. Platelet-activating factor-induced platelet aggregation decreased from 75 ± 7% at wk 0 to 35 ± 21% at wk 8 in the 900-mg group (P = 0.016) and from 72 ± 11 to 40 ± 30% in the 1800-mg group (P = 0.039), but did not change in the placebo group. No effects on A DP- or collagen-induced aggregation could be attributed to EPA-E. In the 1800-mg group low-density-lipoprotein cholesterol increased significantly, without concomitant rise in apolipoprotein B. Triglycerides, glycemic control, lipoprotein (a), blood and plasma viscosity, erythrocyte deformability, and platelet adhesion to and aggregate formation on extracellular endothelial cell matrix were not significantly influenced. CONCLUSIONS Purified EPA-E in doses of 900 and 1800 mg reduces Plateletactivating factor-induced platelet aggregation without negatively affecting glycemic control. Low-density-lipoprotein cholesterol was elevated in the 1800-mg group.

Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients share many clinical and biochemical characteristics. However, sural nerve biopsies from patients with advanced and chronic neuropathy show ultrastructural differences between these two groups. We investigated whether at a subclinical stage of the illness, when Type 1 and Type 2 diabetic patients are clinically uniform and the histopathological nerve alterations are not advanced, comparison between the two diabetes groups might show differences in nerve fibre involvement related to the different pathogeneses of the neuropathies. A total of 88 diabetic patients (52 Type 1 and 36 Type 2), with a subclinical form of polyneuropathy were selected. The clinical neurophysiological examination consisted of motor and sensory nerve conduction studies, Hoffmann (H)-reflex, single fibre electromyography and static as well as dynamic pupillometry. With regard to clinical neurophysiological abnormalities, the severity of the polyneuropathy appeared to be equal in both groups. Despite the absence of clinical symptoms the neurophysiological abnormalities were pronounced and it was impossible to differentiate Type 1 diabetic patients from Type 2 diabetic patients on a clinical neurophysiology basis when correcting for differences in age, height, and duration of illness. In the Type 1 diabetic group as well as in the Type 2 diabetic group the autonomic nerve fibres and nerves in the legs were more frequently affected than the thick myelinated nerves in the arms. These findings do not support the assumption that there is a difference in the manifestation of polyneuropathy between Type 1 and Type 2 diabetic patients.

BACKGROUND Nitric oxide (NO) has been identified as endothelium-derived relaxing factor (EDRF), which, in addition to its relaxant effects on vascular smooth muscle cells, is also a potent inhibitor of platelet aggregation. An inhibitory role on platelet adhesion has been suggested from experiments with washed platelets under static conditions. We have determined whether endothelium-derived and exogenous NO also regulates platelet adhesion in whole blood under flow conditions. METHODS AND RESULTS The effect of endothelium-derived NO was studied by the addition of specific inhibitors of NO production, L-N-monomethyl arginine (L-NMMA) and N-iminoethyl-L-ornithine (L-NIO), to a perfusion system in which both endothelial cells and their matrices were present. A concentration-dependent increase in platelet adhesion to the matrix was found with a maximum inhibition at a concentration of 2 mM L-NMMA and 0.1 mM L-NIO. The effect was dependent on the presence of endothelial cells, because no increase in platelet adhesion was observed in their absence. The effect of exogenous NO was tested in a specially devised perfusion system in which the NO was introduced at the site of adhesion by means of a porous membrane on which an extracellular matrix of endothelial cells was present. Inhibition of platelet adhesion by NO was found at all shear rates tested and after all perfusion periods. CONCLUSIONS These results demonstrate that NO is a potent inhibitor of platelet adhesion under flow conditions and thereby contributes to the regulatory role of vascular endothelial cells on platelet-vessel wall interaction.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

Platelet interaction with subendothelium of human renal and umbilical arteries and with the extracellular matrix produced by cultured human venous endothelial cells was compared in flowing citrated blood by using an annular and a rectangular perfusion chamber. The renal arteries were post mortem specimens from adults showing, often pronounced, intimal fibrosis, whereas the umbilical arteries had well organized parallel arranged smooth muscle cells, without elastic membranes. The extracellular matrix obtained after removal of endothelial cells with Triton X-100 was homogenously attached to its substratum. Significantly more platelets adhered to the extracellular matrix than to the subendothelia. This discrepancy was most pronounced in reconstituted blood with plasma from a patient with homozygous severe von Willebrand's disease (subtype III). No differences in platelet adherence and platelet aggregate formation were noted between the subendothelia. Platelet aggregate formation was poor on all surfaces. These data indicate that the extracellular matrix produced by endothelial cells is at least as reactive for the interaction with platelets as subendothelium, probably partly synthesized by smooth muscle cells.

Fifteen patients suffering from Raynaud's phenomenon (RP) were examined. They were placed in a "climate chamber" (a small room in which the temperature and humidity could be varied). The temperature was gradually decreased, while the humidity was kept constant. After 60-90 min, distinct RP was induced and intravenous medication was administered. The whole trial was performed in a double-blind, cross-over fashion. Every patient participated in two experiments performed 2 days apart. Either ketanserin or placebo was given during the first experiment. In the second experiment, the medication (or placebo) which had not been given was administered. The effects of ketanserin were highly significant: the bluish pallor changed into bright erythema and the skin temperature rose significantly. This was interpreted as a spasmolytic effect. Intravenously administered ketanserin has a place in the clinical treatment of acutely deteriorating RP of diverse etiologies.

Platelet activation in diabetes mellitus may precede vasculopathy. We have studied platelet adhesion and thrombus formation in flowing blood of diabetic patients without macro-and microvascular complications. Platelet function and release, bleeding time, fibrinogen, FVIII:RAg, Ri:Co, Triglycerides, Cholesterol and HDL Cholesterol levels, Apo A, Apo B and TK values were in the normal range. Glucose levels and HBA1 were increased. The matrix of cultured human umbilical vein endothelial cells (ECM) was used for adhesion studies.In an adhesion model with citrated blood (3.1%) and an untreated ECM, three male and three female diabetics (mean age 29.6 y., range 20-32 y., average duration of diabetes 10.6 y., range 2-23 y.) were compared with six age and sex-matched corf-trols. No differences in platelet coverage (en face) was obtained at low (300 s™1 ) and high (1300 s™1 ) wall shear rates, and the time dependence (1-20 min) was the same.We also used a thrombosis model, consisting of the matrix of PMA-treated endothelial cells which induces tissue factor production, perfused with blood anticoagulated with low molecular weight heparin, which does not inhibit local thrombus formation. Four male and two female patients (mean age 25.4 y., range 22-40 y., average duration of diabetes 10 y., range 2-28 y.) were compared with six age and sex matched controls. Cross sections showed equal total adhesion at 300 s™1 and 1300 s™1 after 1, 3, 5 or 10 minutes perfusion. In the diabetics, spread platelets were significantly decreased at 300 s™1 after 1 and 3 min, and at 1300 s™1 after 5 min; small aggregates (< 5μM) were increased after 1 min at 300 s™1 . At 300 s™1 some patients (2 of 6) showed a faster and more extensive fibrin formation.We conclude that _ in this group of diabetics there is no difference in primary adhesion but that there is an enhanced tendency in thrombus formation and fibrin deposition.