Mateja Kaja Jezovnik

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.

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.

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.

Rivaroxaban versus warfarin in the prevention of post-thrombotic syndrome

INTRODUCTION Post-thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that affects 20% to 50% of DVT patients. Standard DVT treatment included vitamin K antagonists (usually warfarin) with low-molecular-weight heparin in the initial period. In recent years, direct oral anticoagulants (DOAC) were introduced. We aimed to investigate the influence of rivaroxaban and warfarin on PTS development. METHODS Consecutive patients treated for DVT were included, 39 were treated with warfarin and 61 with rivaroxaban. We assessed symptoms and signs of PTS and calculated Villalta score 23months (median) after acute DVT diagnosis. Differences between patients treated with rivaroxaban and warfarin were investigated. RESULTS Patients in the rivaroxaban group had a lower prevalence of PTS than those treated with warfarin (25% vs. 49%, p=0.013). Logistic regression showed odds ratio of 2.9 (1.2-6.8, p=0.014) for PTS development in warfarin group compared to rivaroxaban group. When adjusted for other variables, the odds ratio was 3.5 (1.1-11.0, p=0.035). CONCLUSIONS Treatment of DVT with rivaroxaban might be associated with a lower risk for PTS development. A larger randomized trial would be needed for stronger evidence.

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.

Short-Term Experience with Off-Pump Versus On-Pump Implantation of the HeartWare Left Ventricular Assist Device

Implantation of left ventricular assist devices while avoiding cardiopulmonary bypass (CPB) may decrease bleeding and improve postoperative recovery. To understand the effectiveness of this approach, we reviewed the charts of 26 patients who underwent HeartWare left ventricular assist device (HVAD) implantation without use of CPB (off-CPB group) and 22 patients who had HVAD implanted with CPB (CPB group) with an emphasis on the 30 day postoperative period. Preoperatively, both groups had similar demographic, functional, and hemodynamic characteristics. Off-CPB patients had significantly shorter surgery times than CPB patients, 188.5 (161.5–213.3) min versus 265.0 (247.5–299.5) min, respectively; p < 0.001. Blood transfusion requirements during surgery and within the postoperative 48 hour period were significantly lower in the off-CPB group than in the CPB group (odds ratio: 5.9; 95% confidence interval: 1.1–31.1, p = 0.042). Compared with the CPB group, the off-CPB group patients had a shorter intubation time, 21 (17.4–48.5) hours versus 41 (20.6–258.4) hours; p = 0.042. Intensive care unit stay was 7.0 (4.75–13.5) days for off-CPB versus 10.0 (6.0–19.0) days for CPB (p = 0.256). The off-CPB approach allows HVAD to be implanted quickly with significantly less perioperative bleeding and transfusion requirements and facilitates postoperative rehabilitation.

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.

The Role of Inflammatory Biomarkers in the Detection and Therapy of Atherosclerotic Disease.

The estimation of risk for atherosclerotic cardiovascular (CV) 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 or clinical disease. Inflammation mediates all stages of the disease, from initiation to the thrombotic complications of atherosclerosis. Raised levels of several circulating markers, particularly inflammatory mediators, have been reported in subjects with atherosclerosis. Increased risk for CV events is associated with increased levels of cytokines, celladhesion molecules, P-selectin and E-selectin, and acute phase reactants, such a highsensitivity C-reactive protein and serum amyloid-A. Elevation of some of these markers predicts the outcomes of patients with acute coronary syndromes. However, because of their non-specificity, these biomarkers represent only a moderate added predicting value after considering conventional CV risk factors. Consequently, recent research has focused on the detection of vulnerable plaque, using vascular bed-specific biomarkers that can help identify individuals at highest risk and help guide how to intervene to prevent CV events. Considerable progress in the understanding of the role of the inflammation in atherogenesis has opened new possibilities for the management of atherosclerosis. Recently new drugs mediating the direct inhibition of circulating markers of inflammation were developed. These drugs could provide a novel therapeutic approach and further enhance the understanding of the role of inflammation in atherosclerosis.

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.

Endothelial Dysfunction and Venous Thrombosis

Venous thrombosis (VT) is one of the most frequent vascular diseases which most often affects deep (deep vein thrombosis) and superficial veins of lower limbs. Venous thrombosis is a multifactorial disease related to different risk factors. These risk factors predispose apparently healthy patients to venous thromboembolic disease and are likely to trigger thrombotic episodes in patients with prothrombotic tendencies. Acquired or inherited risk factors responsible for thromboembolic events are identifiable in most patients. However, the basic pathogenic mechanisms in venous thromboembolism (VTE) with known or unknown risk factors remain unexplained. The most probable pathophysiological mechanism which cause VTE involve the Virchow triad: endothelial damage, blood stasis, and hypercoagulability. All these pathogenic mechanisms are usually interrelated and most probably the thrombotic process starts with damage of the venous wall. This damage can be caused by mechanical forces (turbulent blood flow or immobilization) or biochemical factors (abnormal constituents of blood, like inflammation mediators, homocysteine, procoagulant factors). Most probably, a functional deterioration of the vessel wall—endothelial dysfunction (ED) is important. Functional capability of the vessel wall, particularly of the endothelium, is an important protective mechanism that ensures circulatory homeostasis and prevents thrombus formation. The main function of the endothelium is to regulate systemic blood flow and tissue perfusion. In addition, the endothelium acts as a barrier that selectively controls the movement of fluids and molecules between circulating blood and surrounding tissue. The endothelium also regulates the recruitment and extravasation of proinflammatory leukocytes in response to tissue damage and infection through the expression of cell adhesion molecules and cytokines. The endothelium is also involved in the recanalization of obstructive fibrin clots. The endothelium expresses different molecules that regulate the activation of platelets and coagulation cascade, maintaining blood flow and preventing thrombus formation after vessel injury. Endothelial dysfunction, which is characterized by an imbalance between relaxing and contracting factors, procoagulant and anticoagulant substances, and between proinflammatory and anti-inflammatory mediators, plays a significant role in the pathogenesis of atherosclerosis and probably also in the development of venous thromboembolic disease. The common mechanism through which different risk factors cause ED is most probably increased oxidative stress and consequent decreased bioavailability of nitric oxide (NO).