Cardiometabolic Risk, Peripheral Arterial Disease and Cardiovascular Events in Polycystic Ovary Syndrome: Time to Implement Systematic Screening and Update the Management.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder in women of reproductive age. It presents with gynaecologic, metabolic, and psychologic manifestations. The dominant drivers of pathophysiology are hyperandrogenism and insulin resistance. Both conditions are related to cardiometabolic risk factors, such as obesity, hypertension, dyslipidaemia, hyperglycaemia, type 2 and gestational diabetes, nonalcoholic fatty liver disease and obstructive sleep apnoea. Women with PCOS of reproductive age consistently demonstrated an elevated risk of subclinical atherosclerosis, as indicated by different measurement methods, while findings for menopausal age groups exhibited mixed results. Translation of subclinical atherosclerosis into the increased incidence of peripheral arterial disease and major cardiovascular (CV) events is less clear. Although several expert groups have advised screening, the CV risk assessment and prevention of CV events are frequently underdiagnosed and overlooked aspects of the management of PCOS. A combination of lifestyle management and pharmacotherapy, including the promising new era of anti-obesity medicine, can lead to improvements in cardiometabolic health.

Preclinical atherosclerosis and cardiovascular events: Do we have a consensus about the role of preclinical atherosclerosis in the prediction of cardiovascular events?

Atherosclerosis has a long preclinical phase, and the risk of cardiovascular (CV) events may be high in asymptomatic subjects. Conventional risk factors provide information for the statistical probability of developing CV events, but they lack precision in asymptomatic subjects. This review aims to summarize the role of some widely publicized indicators of early atherosclerosis in predicting CV events. The earliest measurable indicator of the atherosclerotic process is endothelial dysfunction, measured by flow-mediated dilation (FMD) of the brachial artery. However, reduced FMD is a stronger predictor of future CV events in patients with existing CV disease than in apparently healthy persons. Alternatively, measurement of carotid artery intima-media thickness does not improve the predictive value of risk factor scores, while detection of asymptomatic atherosclerotic plaques in carotid or common femoral arteries by ultrasound indicates high CV risk. Coronary calcium is a robust and validated help in the estimation of vascular changes and risk, which may improve risk stratification beyond traditional risk factors with relatively low radiation exposure. Arterial stiffness of the aorta, measured as the carotid-femoral pulse wave velocity is an independent marker of CV risk at the population level, but it is not recommended as a routine procedure because of measurement difficulties. Low ankle-brachial index (ABI) indicates flow-limiting atherosclerosis in the lower limbs and indicates high CV risk, while normal ABI does not rule out advanced asymptomatic atherosclerosis. Novel circulating biomarkers are associated with the atherosclerotic process. However, because of limited specificity, their ability to improve risk classification at present remains low.

Factors influencing recanalization of thrombotic venous occlusions.

The outcome of a thrombotic vessel occlusion is related to the resolution of thrombus and restitution of blood flow. Thrombus formation simultaneously activates an enzymatic process that mediates endogenous fibrinolysis to maintain vessel patency. The balance between coagulation and fibrinolysis determines the extent of thrombus formation, its resolution, and clinical outcome. Endogenic fibrinolysis is frequently unable to overcome coagulation and to resolve the thrombus. Therefore, for a complete resolution of thrombus in an acute phase, exogenic fibrinolytic agents are needed. Currently, tissue plasminogen activator (tPA) is most frequently used for therapeutic thrombolysis. Also, heparins, particularly low-molecular-weight heparins and direct oral anticoagulants which are known as anticoagulant drugs, have some pro-fibrinolytic properties. Besides the extent and age of a clot, different other factors influence the lysis of thrombus. Thrombus structure is one of the most important determinants of thrombus lysis. The concentration of thrombolytic agent (tPA) around and inside of thrombus importantly determines clot lysis velocity. Further, flow-induced mechanical forces which stimulate the transport of thrombolytic agent into the clot influence thrombolysis. Inflammation most probably represents a basic pathogenetic mechanism of activation of coagulation and influences the activity of the fibrinolytic system. Inflammation increases tissue factor release, platelet activity, fibrinogen concentration and inhibits fibrinolysis by increasing plasminogen activator inhibitor 1. Therefore, recanalization of a thrombotic vessel occlusion is inversely related to levels of some circulating inflammatory agents. Consequently, inhibition of inflammation with anti-inflammatory drugs may improve the efficacy of prevention of thromboembolic events and stimulate recanalization of thrombotic occlusions of veins.

In patients with superficial vein thrombosis the inflammatory response is increased and related to the recanalization rate.

INTRODUCTION: Little is known about pathogenetic mechanisms of superficial venous thrombosis (SVT). We aimed to investigate the systemic inflammatory response in the acute phase of SVT, the time course of inflammatory markers and involvement of inflammation in resolution of thrombus in SVT. MATERIAL AND METHODS: The circulatory inflammatory parameters high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), interleukins 6, 8 and 10 (IL-6, IL-8, IL-10), and markers of fibrinolytic activity tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were determined in 68 patients with acute SVT of lower limbs, who were allocated to two groups, dalteparin 5000 IU once daily or 10 000 IU once daily. Recanalization of occluded veins was monitored by ultrasonography at regular intervals. Blood was drawn in the acute phase and after 12 weeks. RESULTS: In the acute phase a majority of the measured inflammatory markers were increased, while after 12 weeks most of them significantly dropped: hsCRP: 13.6 ±11.9 vs. 7.4 ±4.4, p < 0.001; IL-6: 3.8 ±3.1 vs. 2.6 ±1.9, p = 0.007. Significant changes in endogenic fibrinolytic parameters were also observed: t-PA activity decreased (0.81 ±0.35 vs. 0.68 ±0.34, p = 0.003), while PAI-1 levels increased (5.6 ±5.1 vs. 8.8 ±8.5, p < 0.001). Levels of inflammatory markers at inclusion and after 12 weeks were related to less effective thrombus resolution: CRP: r = 0.386, p = 0.001; IL-6: r = 0.384; TNF-α: r = 0.255, p = 0.037. CONCLUSIONS: In the acute phase of SVT, most of the circulating inflammatory markers were increased and most of their levels decreased after 12 weeks. Levels of inflammatory markers were negatively correlated with the recanalization rate.

Total Hip Replacement Provokes Endothelial Dysfunction.

Surgery represents an increased risk of different perioperative complications. Endothelial function (EF) is a key mechanism responsible for cardiovascular homeostasis and is involved in thromboembolic complications. We aimed to follow changes of EF in an early postoperative period in patients undergoing total hip replacement (THR). Endothelial function was assessed noninvasively in 70 consecutive patients who underwent an elective THR under spinal anesthesia. Flow-mediated dilation (FMD) and low flow-mediated constriction capability of the brachial artery, which are indicators of EF were measured before the operation (baseline), 24 hours after the operative procedure, and 5 to 7 days postoperatively. Baseline FMD was 12.3% and decreased a day after surgery to 7.3% ( P < .001). After 5 to 7 days, it gradually increased to 9.2%. However, on average, it was lower than before surgery ( P < .001). The median duration of THR was 85.0 (65.0-100.0) minutes, the average hospital length of stay was 7 days. Total hip replacement is associated with an immediate decrease in FMD which remains significantly decreased 5 to 7 days after the surgery compared with the preoperative value. These results indicate that surgery provokes endothelial dysfunction and deteriorates cardiovascular homeostasis. This effect could be involved in cardiovascular complications in the postoperative period.

Deep vein thrombosis and properties of the arterial wall.

BACKGROUND: Deep vein thrombosis (DVT) affects more than one out of 1,000 people every year, of which 50 % develop post-thrombotic syndrome (PTS). Studies indicated that patients with DVT have deteriorated arterial wall function, while less is known about the association with PTS. We therefore investigated this relationship further. PATIENTS AND METHODS: A total of 120 patients treated for DVT of the lower extremity and a control group of 40 subjects without DVT were included. We assessed the presence of PTS using the Villalta scale. Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were calculated and reactive hyperaemia index (RHI) and augmentation index (AI) were obtained. RESULTS: Patients with a history of DVT had lower FMD (4.0 % vs. 8.0 %, p < 0.001), lower NMD (12 % vs. 19 %, p = 0.001), and increased diameter of brachial artery (4.8 mm vs. 4.4 mm, p = 0.017). Peripheral arterial tonometry showed higher AI in patients with DVT (22.0 vs. 6.0, p = 0.004), while there was no difference in RHI. No differences in values between PTS-positive and PTS-negative patients were found. CONCLUSIONS: We confirmed the association between DVT and deteriorated functional properties of the arterial wall. Endothelial dysfunction of the large arteries, increased arterial stiffness, and increased diameter of the brachial artery were found in patients with DVT. However, there was no association between functional capability of the arterial wall and the incidence of PTS in DVT patients.

Structure of Atherosclerotic Plaques in Different Vascular Territories: Clinical Relevance.

BACKGROUND: Atherosclerosis is a systemic disease with different faces. Despite similar, or even identical, risk factors and pathogenesis, atherosclerotic lesions and their clinical manifestations vary in different parts of the vasculature. Peripheral arterial disease (PAD) in the superficial femoral artery (SFA) represents a frequent clinical manifestation of atherosclerotic disease. The pathohistological characteristics of plaques in PAD differ from lesions in the coronary arteries. Plaques in the SFA have more fibrotic elements with less lipid and degenerative tissue elements; this makes them more stable and less prone to rupture. The density of vasa vasorum, an important determinant of structure and stability of atherosclerotic lesions, is significantly lower in PAD than in coronary arteries. Further, haemodynamic forces and shear stress vary in different segments of the arterial tree and influence the development of atherosclerotic lesions and their stability. It follows that the clinical consequences differ depending on the vascular territory involved. In the coronary arteries, acute thrombotic occlusion with clinical manifestation of myocardial infarction is one of the most frequent manifestations due to unstable atherosclerotic lesions. Atherosclerotic lesions in SFA progress slowly and are more stable; therefore, clinical manifestations develop more gradually. CONCLUSION: The atherosclerotic process in SFA is frequently asymptomatic or presents as stable intermittent claudication, and in a relatively low percentage, progresses to critical limb ischaemia. Also, remodelling of the arterial wall in peripheral arteries compensates for the reduction of arterial lumen and provides blood flow in spite of relatively large atherosclerotic lesions. However, arterial restenosis after recanalization procedures in SFA reduces the long-term success of recanalization.

Deep Vein Thrombosis and Pulmonary Embolism in the Apixaban Era: From Bench to Bedside.

BACKGROUND: The traditional treatment of venous thromboembolism (VTE) with heparin and warfarin has numerous limitations. New oral anticoagulants represent the promising alternative with the potential to overcome the limitations of traditional treatment. OBJECTIVE: Apixaban is an oral factor Xa inhibitor with a rapid onset of action and predictable pharmacokinetics that allows a fixed dose regimen. With this characteristic apixaban overcomes many limitations and simplifies treatment of VTE eliminating the need for initial parenteral anticoagulant therapy and laboratory monitoring. RESULTS: Fixed-dose regimen of oral apixaban alone is as effective as conventional treatment regimen and is associated with a clinically relevant reduction of major bleeding. Extended anticoagulation with apixaban with either a treatment dose (5 mg twice daily) or thromboprophylactic dose (2.5 mg twice daily) reduces the risk of recurrent venous thromboembolism without increase in the rate of major bleeding. CONCLUSION: Therefore, apixaban provides a simple, effective and safe alternative to conventional acute or long-term treatment of VTE.

Insufficient Recanalization of Thrombotic Venous Occlusion-Risk for Postthrombotic Syndrome.

PURPOSE: To investigate the relationship between recanalization rate of occluded veins after deep venous thrombosis (DVT) and development of postthrombotic syndrome (PTS). MATERIALS AND METHODS: Patients treated for DVT of the lower limbs were evaluated 12-36 months after acute DVT. Of 100 patients, 34 developed PTS, defined as Villalta score of ≥ 5. Symptoms and signs of PTS were assessed, and ultrasound examination of the veins was performed, checking for residual thrombus and presence of reflux. RESULTS: Patients with PTS were older (64.0 y vs 55.5 y; P = .007) and more frequently experienced recurrent DVT (15% vs 3%; P = .030). Patients with PTS had a lower rate of recanalization. Patients with residual thrombus appeared to be at increased risk for PTS development compared with patients with total recanalization (odds ratio 6.0; 95% confidence interval, 1.7-21.9; P = .006). No difference in the presence of reflux was observed. CONCLUSIONS: Incomplete or absent recanalization is associated with a higher incidence of PTS, probably as a consequence of deteriorated blood flow and increased venous pressure. This suggests early recanalization could improve the outcome of DVT treatment in selected patients.

Patients With a History of Idiopathic Deep Venous Thrombosis Have Long-Term Increased Levels of Inflammatory Markers and Markers of Endothelial Damage.

INTRODUCTION: Although the role of inflammation in DVT has been investigated in different studies, there is no definite answer as to whether increased systemic inflammation is the cause or the consequence of DVT. AIM: To follow inflammatory parameters in a cohort of patients with idiopathic DVT. METHODS: Out of 49 patients with an acute idiopathic DVT, which were investigated four months after an acute episode (DEVTA 1), 43 patients were included in the follow-up study investigating inflammatory markers and hemostatic markers of endothelial damage five years after an acute DVT (DEVTA 2). A control group consisted of 43 sex and age matched healthy subjects (CONTROLS). RESULTS: The levels of inflammatory markers were significantly higher in DEVTA 2 in comparison to CONTROLS: tumor necrosis factor alpha 2.0 pg/mL (1.1-2.3) vs 1.3 pg/mL (0.8-1.9), p < .001, high sensitivity C-reactive protein 3.2 mg/L (1.5-5.2) vs 1.7 mg/L (0.9-3.0), p = .008, interleukin-6 (IL-6) 2.7 pg/mL (2.0-3.5) vs 2.1 pg/mL (1.5-2.6), p = .025, IL-8 5.0 pg/mL (3.6-7.3) vs 2.4 pg/mL (1.8-2.8), p < .001. IL-10 was significantly decreased (0.9 pg/mL (0.7-1.8) vs 1.8 (1.5-2.2), p < .001. Most of the proinflammatory markers remained elevated in the DEVTA 2 in comparison to DEVTA 1. Markers of endothelial damage were higher in DEVTA 2 in comparison to CONTROLS and higher than in DEVTA 1. CONCLUSION: Patients with idiopathic DVT have long-term increased inflammatory markers and markers of endothelial damage. These findings favor the hypothesis that inflammation is a cause and not merely a consequence of acute DVT.

Patients with an Inflamed Atherosclerotic Plaque have Increased Levels of Circulating Inflammatory Markers.

AIM: Inflammation is highlighted in the pathogenesis and destabilization of atherosclerotic lesions. Noninvasive identification of inflammation of atherosclerotic lesions has been challenging. 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a useful technique for detecting inflamed atherosclerotic plaques in vivo. However, it is time consuming, expensive, and accompanied by radiation. Therefore, we investigated the relationship between levels of circulating inflammatory markers and the degree of inflammation of atherosclerotic plaques shown by 18F-FDG uptake. We aimed to identify high-risk patients with inflamed, unstable atherosclerotic plaques on the basis of the determination of inflammatory markers. METHODS: The study included 37 patients, 21 with high-grade stenosis of internal carotid artery (ICA group) and 16 with occlusion of common femoral artery (CFA group), who underwent endarterectomy. Mean age of the study population was 69.43±6.2 years. Eight out of 21 patients with ICA stenosis and all patients with CFA occlusion were symptomatic. In all patients before endarterectomy, 18F-FDG-PET imaging was performed and blood samples were obtained for determination of circulating inflammatory markers: high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), interleukins, and selectins. Both groups were compared with a sex- and age-matched control group composed of 27 healthy volunteers. RESULTS: 18F-FDG uptake, calculated by target-to-background ratio (TBR) was not significantly different between the groups. Levels of inflammatory markers were elevated, and there were no significant differences between ICA and CFA groups, with an exception of interleukin 6 (IL-6) levels, which was higher in the ICA group (3.2±2.5 ng/L vs. 1.8±1.3 ng/L, p＜0.05). There was a positive interrelationship between 18F-FDG-PET and most of the systemic inflammatory markers: hsCRP (r=0.417, p=0.010), IL-6 (r=0.603, p＜0.001), and TNF-α (r=0.374, p=0.023). However, correlation between 18F-FDG-PET and P-selectin, E-selectin, and t-PA was not found. CONCLUSION: Our study showed that an interrelationship exists between the intensity of inflammatory process of atherosclerotic lesions shown by FDG uptake and circulating inflammatory markers. Therefore, the determination of circulating inflammatory markers can have a potential to identify individuals with unstable, inflamed atherosclerotic plaques.

Markers of preclinical atherosclerosis and their clinical relevance.

The estimation of risk for atherosclerotic and cardiovascular events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical disease in individual subjects: blood markers of atherosclerosis and preclinical deterioration of the arterial wall. Elevated levels of several inflammatory mediators have been found in subjects with atherosclerosis. Increased basal levels of cytokines, the cell adhesion molecules, selectins and acute-phase reactants such as high sensitive C-reactive protein (hsCRP), fibrinogen, and serum amyloid A are related to an increased risk of cardiovascular events. For clinical purposes, the most promising inflammatory biomarker appears to be hsCRP. In the last decade, markers of plaque stability and unstable coronary artery disease have been sought. Further, markers of endothelial dysfunction, like circulating molecules as well as indicators of functional deterioration of the arterial wall were identified. It was shown that endothelial dysfunction is closely related to different risk factors of atherosclerosis, and to their intensity and duration. Intima-media thickness measurement has emerged as one of the methods of choice for determining the anatomic extent of preclinical atherosclerosis and for assessing cardiovascular risk.Determination of markers of preclinical atherosclerosis improve individual risk determination and could influence the decision of a clinician to intervene with medication and to use more aggressive treatment of risk factors in high risk subjects and in patients with atherosclerotic disease.

Do the Effects of Secondary Prevention of Cardiovascular Events in PAD Patients Differ from Other Atherosclerotic Disease?

Atherosclerosis is considered a generalized disease. Similar or identical etiopathogenetic mechanisms and risk factors are involved in various atherosclerotic diseases, and the positive effects of preventive measures on atherogenesis in different parts of the arterial system were shown. However, until know, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease (CHD), while less attention has been devoted to the management of peripheral arterial disease (PAD), despite its significant morbidity and mortality. Data on the efficacy of preventive measures in PAD patients have mostly been gained from subgroup analyses from studies devoted primarily to the management of coronary patients. These data have shown that treatment of risk factors for atherosclerosis with drugs can reduce cardiovascular events also in patients with PAD. The effects of some preventive procedures in PAD patients differ from coronary patients. Aspirin as a basic antiplatelet drug has been shown to be less effective in PAD patients than in coronary patients. The latest Antithrombotic Trialists' Collaboration (ATC) meta-analysis demonstrates no benefit of aspirin in reducing cardiovascular events in PAD. Statins reduce cardiovascular events in all three of the most frequently presented cardiovascular diseases, including PAD to a comparable extent. Recent studies indicate that in PAD patients, in addition to a reduction in cardiovascular events, statins may have some hemodynamic effects. They prolong walking distance and improve quality of life. Similarly, angiotensin enzyme inhibitors are also effective in the prevention of cardiovascular events in coronary, cerebrovascular, as well as PAD patients and show positive effects on the walking capacity of patients with intermittent claudication. In PAD patients, the treatment of hypertension and diabetes also effectively prevents cardiovascular morbidity and mortality. As PAD patients are at a highest risk of cardiovascular complications, the risk factors of atherosclerosis should be treated intensively in this group of patients. Most of the preventive measures, including the drugs used for prevention of CHD, are also effective in PAD patients.

Time course and the recanalization rate of superficial vein thrombosis treated with low-molecular-weight heparin.

The aim of this study was to follow the thrombus progression and regression in superficial veins of lower limbs in patients with superficial vein thrombosis (SVT) treated with low-molecular-weight heparin. Patients (n = 68) with a first symptomatic SVT of the lower limbs received 2 different dosages of dalteparin. The primary outcome was a change in the diameter and length of thrombus in the affected veins. The regression of thrombus was not significantly different between the groups (P = .19). The reduction in the length of thrombus as well as thrombus diameter was significantly greater in females. At the end of the observation period, the length of thrombus in the distal part was more reduced than in the proximal segments. It seems that the dosage of anticoagulant drug does not have a significant impact on thrombus resolution.

Identification of inflamed atherosclerotic lesions in vivo using PET-CT.

Inflammation plays a major pathogenetic role in the development of atherosclerotic plaques and related thromboembolic events. The identification of vulnerable plaques is of the utmost importance, as this may allow the implementation of more effective preventive and therapeutic interventions. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for tracing inflammation within plaques. However, its relationship to immunohistochemical findings in different territories of the peripheral circulation was not completely elucidated. We aimed to determine whether plaque inflammation could be measured by PET in combination with computer tomography (CT) using FDG and what is the relationship between FDG uptake and immunohistochemical findings in the removed atherosclerotic lesions of the femoral and carotid arteries. The study included 31 patients, 21 patients with high-grade stenosis of the internal carotid artery (ICA) and 10 patients with occlusion of the common femoral artery (CFA), all of whom underwent endarterectomy. Before endarterectomy in all patients, FDG-PET/CT imaging was performed. FDG uptake was measured as the maximum blood--normalized standardized uptake value, known as the target to background ratio (TBR max). TBR max amounted to 1.72 ± 0.8, and in patients with ICA, stenosis was not significantly different from patients with CFA occlusion. Immunohistochemical and morphometric analyses of the plaques obtained at endarterectomy showed that the density of T lymphocytes and macrophages (number of cells per square millimeter) was significantly higher in subjects with stenosis of the ICA than in subjects with occlusion of the femoral arteries: lymphocytes, 1.26 ± 0.21 vs. 0.77 ± 0.29; p = 0.02 and macrophages, 1.01 ± 0.18 vs. 0.69 ± 0.23; p = 0.003. In the whole group of patients, the density of inflammatory cells significantly correlated with FDG uptake represented by PET-TBR max: T lymphocytes, r = 0.60; p < 0.01 and macrophages, r = 0.65; p < 0.01. The results of our study show that FDG uptake is related to the accumulation of inflammatory cells in atherosclerotic lesions. This finding suggests that FDG uptake reflects the severity of atherosclerotic vessel wall inflammation, and in stenotic lesions, it could be an indicator of their vulnerability. However, data from large outcome studies is needed to estimate the usefulness of this technique in identifying the most dangerous atherosclerotic lesions and vulnerable patients.

Testing endothelial function and its clinical relevance.

Endothelial dysfunction as an integrating index of the risk factor burden and genetic susceptibility is an early marker of atherothrombotic disease. Therefore, tremendous interest exists in its measurement and determination of the clinical utility of the evaluation of endothelial function.Different invasive and non-invasive techniques exist for exploring various aspects of the pathobiology of the endothelium. As endothelial dysfunction is a diffuse-systemic disorder, the peripheral arteries, because of their accessibility, represent the basis for assessment of endothelial dysfunction. Flow-mediated dilation (FMD) of the peripheral conduit arteries is one of the most widely used tests of endothelial function. FMD measures the endothelial vasomotor response during reactive hyperemia, but it does not provide information concerning the control of arterial tone at rest. A new technique, low-flow-mediated constriction (L-FMC), provides complementary information to that by FMD, quantifying the decrease in the forearm conduit artery diameter that occurs in response to the decrease in blood flow during occlusion. This indicated that the L-FMC response is not based on nitric oxide availability but it might be mediated by other substances, providing a coordinated effect of vasodilation and its inhibition; therefore, simultaneous determination of FMD and L-FMC may provide comprehensive information on vascular homeostasis.Peripheral arterial tonometry (PAT) evaluates pulse wave amplitude, which is linked to endothelial function. Like FMD, PAT has also been shown to be reduced in the presence of risk factors, as well as in patients with atherosclerosis; however, FMD of the brachial artery and PAT are very different methods for identification of the vascular reactivity of different arterial territories. FMD directly registers the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to the endothelial function of small arteries and to the endothelial function of the microcirculation. Therefore, this technique is mostly used for investigation of the functional capability of the microcirculation.Determination of venous endothelial dysfunction is more complicated and invasive and is less reproducible. Micro-invasive techniques such as the dorsal hand vein technique and radionuclide assessment of changes in volume of the legs provide limited information about venous endothelial health; however, as endothelial dysfunction is expected to be a systemic disorder affecting the complete circulatory system, determination of the endothelial function of peripheral arteries also gives insight into venous functional status.

Dyslipidemia, statins, and venous thromboembolism.

Venous thromboembolism (VTE) is one of the most frequent and serious vascular diseases. Although the major risk factors of VTE are well recognized, the pathology often develops in subjects without any obvious precipitating factor. Recent evidence suggests a link between arterial and venous thrombosis, particularly in patients with idiopathic venous thrombosis. Therefore, similar or identical risk factors may play a role in the development of both diseases. A positive association between classical risk factors of atherosclerosis, including dyslipidemia, and VTE has been reported. Recent studies demonstrated an association between hypercholesterolemia and objectively verified VTE. Circulating lipids have been shown to have both prothrombotic- and endothelium-deteriorating properties. Studies suggested a greater generation of thrombin, endothelial dysfunction, and higher platelet activity in hyperlipidemic blood. By impeding these mechanisms, statins may protect against VTE. Observational, controlled studies and two meta-analyses showed that statins significantly reduced VTE risk, most likely in a process independent from cholesterol lowering, through mechanisms related to the pleiotropic effects of these drugs. Currently, it is unknown whether VTE prevention is a class-effect of statins, or if statins differ in their antithrombotic efficacy, and it is also unknown if statin benefit is dose-dependent. However, there are also opposite findings about the efficacy of statins in prevention of VTE. Therefore, the use of statins for prophylaxis of VTE cannot be generally recommended at this stage. Further studies are needed to identify those patients who could eventually benefit maximally from treatment with statins for prevention of VTE.

In patients with idiopathic venous thrombosis, interleukin-10 is decreased and related to endothelial dysfunction.

The aim of this study was to evaluate the levels of anti-inflammatory interleukin-10 and pro-inflammatory cytokines and their relationship to endothelial function in patients with idiopathic venous thrombosis. Forty-nine eligible patients of both sexes with idiopathic venous thrombosis and 48 matched control subjects were studied. Levels of inflammatory markers were determined. Endothelial function was evaluated by ultrasound measurement of the flow mediated dilatation (FMD) of the brachial artery. Compared to the control group, patients with idiopathic venous thrombosis had significantly lower levels of interleukin-10 1.81 pg/ml (1.53-2.21) versus 2.71 pg/ml (1.84-3.65), p < 0.001. Patients also had increased levels of pro-inflammatory cytokines: interleukin-6 2.37 pg/ml (1.59-4.09) versus 2.03 pg/ml (1.49-2.59), p = 0.025, interleukin-8 3.53 pg/ml (2.94-5.30) versus 2.25 pg/ml (1.77-2.90), p < 0.001. Furthermore, decreased FMD was observed in patients: 5.0% (3.9-6.9) versus 12.7% (10.8-15.6), p < 0.001. FMD was related to levels of interleukin-10 (r = 0.33, p = 0.001) and was inversely related to pro-inflammatory cytokines interleukin-6 (r = -0.34, p = 0.001) and interleukin-8 (r = -0.43, p < 0.001). Patients with idiopathic venous thrombosis have decreased levels of IL-10 and increased levels of pro-inflammatory cytokines. This imbalance indicates that in the stable phase of the disease, patients have an increased systemic inflammatory response. This inflammatory response could be the consequence of the disease, but most probably is involved in the pathogenesis of venous thrombosis.

Impairment of the vasodilatation capability of the brachial artery in patients with idiopathic venous thrombosis.

AIM: Determination of the functional capability of the peripheral arteries is increasingly used as an early marker of vessel disease. The aim of this study was to evaluate flow-mediated (FMD) and glyceryl trinitrate-mediated (NMD) dilation of the brachial artery in patients with idiopathic venous thrombosis (VT). METHODS: Flow-mediated brachial artery dilatation and the dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 97 subjects (49 eligible patients of both sexes, mean age 51.5 ± 14.6 years, with idiopathic venous thrombosis, and 48 age-matched healthy controls). RESULTS: Compared to the control group, FMD was significantly reduced in the group of patients with idiopathic venous thrombosis -4.9% (95% CI 1.1-8.7%) vs. 12.7% (95% CI 7.8-17.6%), p<0.001. Patients also had diminished NMD of the brachial artery -12.5% (95% CI 6.6-18.4%) vs. 18.5% (95% CI 10.1-26.9%), p<0.001. In patients, significantly higher levels of circulatory markers (P-selectin, von Willebrand factor) of endothelial dysfunction were registered. CONCLUSIONS: Idiopathic venous thrombosis is associated with impaired flow- and GTN-mediated vasodilatory response of the brachial artery. This may suggest involvement of the functional deterioration of the vessel wall in the pathogenesis of idiopathic VT and indicate a relationship between VT and atherothrombosis.