Endocrine Disorders and Peripheral Arterial Disease - A Series of Reviews Cushing Syndrome-Cortisol Excess.

Cushing syndrome (CS), characterised by endogenous or exogenous glucocorticoid hormone excess, is associated with several systemic complications, including impaired glucose metabolism, which often becomes clinically manifest as diabetes mellitus (DM). In addition, CS can harm the arterial wall because of hyperglycaemia, dyslipidaemia, hepatic steatosis, and central obesity. These metabolic disorders promote atherosclerosis by synthesising adipokines, leptin, and proinflammatory cytokines. Lower limb arterial complications in CS are common and significantly impact morbidity and mortality. Furthermore, CS, in combination with DM, is likely to cause more diffuse vascular disease that predominantly affects distal arterial beds. In conclusion, CS promotes atherosclerosis, including peripheral artery disease, by causing functional and morphological deterioration of the arterial vessel wall and increasing the presence of classical risk factors of atherosclerosis.

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.

Do blood constituents in varicose veins differ from the systemic blood constituents?

OBJECTIVE: Varicose veins represent one of the most frequent vascular diseases and are in most cases benign. However, advanced disease is frequently associated with complications such as chronic venous insufficiency and superficial vein thrombosis. The pathogenic mechanisms are not well understood. Besides increased venous pressure, it is suggested that local blood constituents trigger various mechanisms responsible for the progression of the disease and its complications. DESIGN: The aim of this study was to investigate the changes in the blood in varicose veins and to compare them with the systemic markers of inflammation and endothelial damage. MATERIALS AND METHODS: Forty patients with primary varicose veins were included in the study. Most patients were class C2. Blood samples were taken from the leg from the tortuous and dilated varicose tributaries of the great saphenous vein and from the cubital vein. RESULTS: The values of basic hematologic tests were comparable between blood samples (varicose vs. systemic). In varicose veins, the following parameters were significantly increased in comparison with systemic blood: hsCRP (3.12 ± 2.18 mg/L vs. 2.04 ± 2.21 mg/L, p = .04), IL-6 (3.54 ± 2.59 pg/mL vs. 2.25 ± 1.27 pg/mL, p = .008), vWF (118.4  ±  27% vs. 83.2  ±  22%, p < .05). D-dimer, in samples taken from the leg varicose veins, was also significantly higher than in the systemic blood (104.3 ± 9.3 ng/mL vs. 89.5 ± 8.3 ng/mL, p = .039). CONCLUSIONS: Some inflammatory markers and indicators of endothelial dysfunction are increased in varicose vein blood. This is most probably the consequence of deteriorated blood flow in dilated and tortuous superficial veins, and increased venous pressure. Damage to the venous wall, which causes a chronic inflammatory response, together with the procoagulant properties of local blood may promote further progression of the disease and thrombotic complications.

Medical management of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is one of the most frequent manifestations of atherosclerosis and is associated with atherosclerosis in the coronary and carotid arteries, leading to a highly increased incidence of cardiovascular events. Major risk factors of PAD are similar to those that lead to atherosclerosis in other vascular beds. However, there are differences in the power of individual risk factors in the different vascular territories. Cigarette smoking and diabetes mellitus represent the greatest risks of PAD. For prevention of the progression of PAD and accompanying cardiovascular events similar preventative measures are used as in coronary artery disease (CAD). However, recent data indicate that there are some differences in the efficacy of drugs used in the prevention of atherothrombotic events in PAD. Antiplatelet treatment is indicated in virtually all patients with PAD. In spite of the absence of hard evidence- based data on the long term efficacy of aspirin, it is still considered as a first line treatment and clopidogrel as an effective alternative. The new antiplatelet drugs ticagrelol and prasugrel also represent promising options for treatment of PAD. Statin therapy is indicated to achieve the target low density lipoprotein cholesterol level of ≤2.5 mmol/L (100 mg/dL) and there is emerging evidence that lower levels are more effective. Statins may also improve walking capacity. Antihypertensive treatment is indicated to achieve the goal blood pressure (<140/90 mmHg). All classes of antihypertensive drugs including beta-blockers are acceptable for treatment of hypertension in patients with PAD. Diabetic patients with PAD should reduce their glycosylated haemoglobin to ≤7%. As PAD patients represent the group with the highest risk of atherothrombotic events, these patients need the most intensive treatment and elimination of risk factors of atherosclerosis. These measures should be as comprehensive as those in patients with established coronary and cerebrovascular disease.

Factors influencing the recanalisation rate of deep venous thrombosis .

AIM: After an acute episode of deep venous thrombosis (DVT) resolution of venous thrombi is followed. However, the complete recanalisation occurs only in about a half of the patients. Therefore, the disease is accompanied by different sequellae like post-thrombotic syndrome. Factors that contribute to lysis of thrombi remain poorly understood. Therefore, the aim of our study was to investigate whether levels of the circulating inflammatory markers and other factors like fibrinolytic parameters, sex, and extent of the thrombotic occlusion are related to the recanalisation rate. METHODS: The study included 49 patients with idiopathic DVT in the stable phase of the disease (4-6 months after the diagnosis). All patients were evaluated for the presence of risk factors of atherosclerosis. Using Duplex ultrasound patients were examined in acute phase of the disease (before start of treatment), and at the end of the observation period (after 4 to 6 months). Each affected venous segment was classified as completely recanalised, partially obstructed, or completely occluded. Blood was collected for laboratory analysis of the fibrinolytic activity and circulating inflammatory markers. RESULTS: Complete recanalisation occurred more frequently in distal (popliteal) than in proximal venous thrombosis (57% vs. 43%, P≤0.01), and the recanalisation rate was lower in patients with more extended thrombosis (increased thrombus load). The recanalisation rate (partial and total) was higher in females than in males: 87% vs. 73%, P=<0.05. Risk factors of atherosclerosis had no influence on the recanalisation rate of the occluded deep veins. Out of the endogenic fibrinolytic markers, t-PA activity only was significantly related to the recanalisation rate. The recanalisation was shown to be related to some circulating cytokines. The multivariate analysis, including inflammatory markers and the recanalisation of deep veins as dependent variables showed that IL-6 and P-selectin were the only statistically significant independent predictors of the recanalisation rate. CONCLUSION: The results of our study show that 4 - 6 months after an acute episode of DVT complete recanalisation of the occluded veins occurred in about 50%. The recanalisation rate is related to the extent of venous thrombosis, is lower in proximal occlusions and is higher in females than in males. In patients with increased cytokine levels and decreased t-PA activity recanalisation is less likely.

Nurr1 haplotypes are associated with femoropopliteal restenosis/re-occlusion after percutaneous transluminal angioplasty.

Restenosis/re-occlusion remains a frequent complication in the first year after percutaneous transluminal angioplasty (PTA). In this study, association of nuclear receptor related 1 protein (Nurr1) haplotypes to the restenosis/re-occlusion rate after femoropopliteal PTA was investigated. Patients (n = 142) with disabling claudication or critical limb ischaemia, who had undergone technically successful femoropopliteal PTA, were prospectively followed up by vascular ultrasound imaging 12 months after the procedure. Nurr1 haplotypes 2 and 3 were associated significantly with the restenosis/re-occlusion rate (adjusted odds ratio 1.6, 95% confidence interval (CI) 1.1-2.3 and 2.0, 1.3-2.8, respectively) on univariate analysis.

Enlargement of the diameter of the peripheral arteries in patients with idiopathic venous thrombosis.

PURPOSE: Recent findings indicate that enlargement of the diameter of the peripheral arteries represents a risk of atherosclerotic cardiovascular events. As the data indicate a relationship between atherosclerosis and venous thrombosis (VT), we investigated whether the diameter of the peripheral arteries is larger in patients with idiopathic VT than in healthy subjects. MATERIALS AND METHODS: The study included 49 patients with idiopathic VT and 48 age-matched healthy controls. Diameters of the brachial, common carotid and common femoral arteries as well as the intima media thickness (IMT) of the carotid and femoral arteries were measured with the high frequency ultrasound method. RESULTS: Patients had significantly higher values for the diameter of the common carotid artery than the controls: 7.9 mm (7.4 - 8.4 mm) vs. 7.4 mm (7.0 - 7.9 mm), p < 0.001, and for the common femoral artery: 10.3 mm (9.2 - 11.1 mm) vs. 9.5 mm (8.9 - 10.4 mm), p = 0.025. Both the carotid and femoral diameters showed significant correlations with gender, age, body mass index and IMT. Linear regression analysis confirmed that the presence of VT significantly and independently influenced the diameter of the carotid and femoral artery but not the brachial artery. CONCLUSION: The results of our study showed that carotid and femoral artery diameters are enlarged in patients with idiopathic VT in comparison to healthy subjects. Since enlargement of the investigated arterial diameters is an indicator of atherosclerosis, our findings are consistent with the presumption that there is some interrelationship between VT and arterial atherosclerotic disease.

Endothelium-dependent and independent dilation capability of peripheral arteries in patients with systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVES: The study evaluated the systemic inflammatory response and endothelium-dependent and independent function of the brachial artery (BA) in systemic lupus erythematosus (SLE) patients with and without antiphospholipid syndrome (APS). METHODS: The study group consisted of 42 women with SLE (21 without APS; mean age 36.1 ± 9.1, and 21 with APS; mean age 43.9 ± 13.1) and 22 healthy controls (mean age 43.5 ± 10.3). Endothelium-dependent functional response was evacuate using the flow-mediated vasodilatation (FMD) of brachial artery and endothelium-independent vasodilatation by application of glyceryl trinitrate (GTN). Using biochemical methods, circulating inflammatory markers were determined. RESULTS: In comparison to controls, in both groups of patients endothelium-dependent dilation of BA was significantly reduced, and there were no differences in FMD between patients with or without APS: SLE - 7.7% (11.9-12.1), SLE+APS 7.8% (2.4-12.8), controls - 14.6% (11.2-21.1), p<0.001. However, endothelium-independent dilation of the brachial artery was significantly lower in SLE-APS patients than in controls and also lower than in the SLE group: SLE - 24.3% (15.0-28.6), SLE+APS-17.4% (13.1-22.6), controls - 23.0% (17.8-30.1), p=0.015 vs. p=0.027. Patients with SLE had significantly higher values of VCAM-1, hs-CRP, and fibrinogen than controls. In patients with SLE+APS, an additional significant increase of inflammatory markers was registered. CONCLUSIONS: The results of our study indicate that patients with SLE have deteriorated endothelium-dependent and those with APS also independent vascular function which could be, together with increased inflammatory response, involved in vascular complications in these patients. The presence of APS aggravates systemic inflammatory response.

Therapeutic equivalence of the generic and the reference atorvastatin in patients with increased coronary risk.

AIM: Generic drugs are more and more frequently used instead of originators. However, uncertainty exists with respect to therapeutic equivalence of generic product with originator one. Therefore, in this study efficacy and safety of generic atorvastatin was compared to reference product. In patients with increased low density lipoprotein cholesterol (LDL-C) levels of cholesterol and changes of total coronary risk were followed. METHODS: A randomized, double-blind, multicenter parallel study was carried out in 22 centers. The study included 148 subjects with LDL-C higher than 3 mmol/L and increased coronary risk (>9.5% in 10 years calculated according to PROCAM algorithm). After a four-week placebo run-in period, patients were randomly assigned to receive the generic or the reference atorvastatin for 12 weeks. The initial dose of the drugs was 10 mg or 20 mg depending on the baseline LDL-C value. After six weeks the dose was increased to 20 mg or 40 mg in patients who had not reached the target LDL-C value of 2.99 mmol/L. RESULTS: Altogether 117 patients have been analysed in the per-protocol analysis. The GA was proven to be equally effective to the reference product as shown by the significantly equal reduction in LDL-C (GA: 37.8%, RA: 38.4%, P=NS) using the non-inferiority statistical analysis. Also other lipid parameters were significantly lowered by both drugs with the exception of HDL-C. Both drugs significantly reduced absolute coronary risk by 13% and 13.3% for the generic and the reference atorvastatin, respectively. Systolic blood pressure was also significantly reduced by approximately 10 mmHg in both study groups. Both products had similar adverse events profile. No cases of therapy withdrawal due to safety were recorded. CONCLUSION: Both the generic and the reference atorvastatin were equally effective in correcting the lipid profile and reducing calculated absolute coronary risk in patients with hyperlipidemia and increased coronary risk. Both treatments were equally well tolerated.

Idiopathic venous thrombosis is related to systemic inflammatory response and to increased levels of circulating markers of endothelial dysfunction.

AIM: During the past decade, the role of inflammation in the pathophysiology of arterial thrombosis has been elucidated. However, little is known about the relationship between inflammation and venous thrombosis. Recently, inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins. The aim of the present study was to investigate the inflammatory markers and their relationship to idiopathic venous thrombosis. METHODS: Fourty-nine patients with first idiopathic venous thrombosis and 48 age matched control subjects were included in the study. Patients were studied 2-4 months after the acute event. Patients and control subjects did not differ in the classical risk factors of atherosclerosis, except in body mass index. In both groups, blood markers of inflammation, namely high sensitive C-reactive protein (hs CRP), interleukins (IL-6, IL-8) and tumour necrosis factor alpha (TNF-a), and circulating markers of endothelial dysfunction/damage namely von Willebrand factor (vWF), P-selectin and the vascular adhesion molecule (VCAM-1) were measured. RESULTS: In comparison to healthy subjects patients had significantly higher levels of inflammatory markers: hs CRP: 2.58 mg/L (1.37-6.61), vs. 1.67 mg/L (0.97-3.24) P=0.044, IL-6: 2.37 pg/mL (1.59-4.10), vs. 2.03 pg/mL (1.45-2.59), P=0.025, IL-8: 3.53 pg/mL (2.94-5.3), vs. 2.25 pg/mL (1.77-2.90) P < or = 0.0001. However, concentrations of TNF-a did not differ significantly between the groups. Also in patients higher levels of circulating markers of endothelial dysfunction: vWF 150.0 g/L (121.0-195.0) vs. 91.5 g/L (70.5-104.0), P < or = 0.0001, P-selectin 39.5 pg/L (34.0-40.6) vs. 34.8 pg/L (32.5-38.6) P=0.009. In contrast, levels of VCAM-1 were comparable between the groups. The levels of some inflammatory markers were related to the concentration of von Willebrand factor and P-selectin - IL-6: vWF (r=0.36, P=0.08), hs CRP: P-selectin (r=0.44, P=0.018), IL-6: P-selectin (r=0.51, P=0.0002), IL-8: P-selectin (r=0.38, P=0.043). CONCLUSION: Patients with idiopathic venous thrombosis have increased levels of circulating markers of inflammation and blood markers of endothelial dysfunction. Higher levels of both groups of markers indicate that patients in the stable phase of the disease have an increased systemic inflammatory response. The interrelationship between inflammatory markers and markers of endothelial dysfunction favour the hypothesis that inflammation could be involved in the etiopathogenesis of idiopathic venous thrombosis.

Infrapopliteal run-off and the outcome of femoropopliteal percutaneous transluminal angioplasty.

BACKGROUND: The outcome of percutaneous transluminal angioplasty (PTA) of peripheral arterial lesions is influenced by several factors, including the haemodynamic conditions. Our study tested: (a) whether infrapopliteal run-off after completed PTA influenced the time course of restenosis/reocclusion of the femoropopliteal arterial segment, and (b) whether worsening of infrapopliteal run-off influenced the long-term femoropopliteal patency after PTA. PATIENTS AND METHODS: Among 245 patients treated by femoropopliteal PTA we enrolled 176 patients who consented to regular follow-up. Concomitant infrapopliteal PTA was performed whenever feasible. The technical success of PTA and the patency of calf arteries were assessed by angiography. Infrapopliteal run-off was scored by a modification of the Society for Vascular Surgery criteria. The treated patients' limbs were divided into a group with good infrapopliteal run-off and a group with compromised run-off. Follow-up examination of the femoropopliteal arterial segment was performed by vascular ultrasonography (US) 1, 6 and 12 months after PTA, and an adverse outcome was defined by a > or = 50 % stenosis, i.e., at least doubling of the maximal systolic velocity, or occlusion - evidenced by the absence of flow. The patency of calf arteries was re-assessed by US 12 months after PTA. RESULTS: One month after femoropopliteal PTA 19 / 83 (23 %) of patients with compromised run-off developed the combined end-point of restenosis or reocclusion in comparison to 10 / 93 (11 %) with good run-off (p = 0.03). After 6 months the incidence of restenosis/reocclusion had increased in both groups at an approximately equal rate, but the differences were no longer significant: 39 / 80 (49 %) in the compromised run-off group vs. 36 / 83 (43 %) in the good run-off group after 6 months, p = 0.49, and 42 / 73 (57 %) vs. 38 / 73 (52 %) after 12 months, p = 0.51. However, in patients' limbs with good periprocedural run-off that deteriorated into compromised run-off in the year after PTA, femoropopliteal restenosis/reocclusion occurred more often than in limbs which retained good run-off: 10 / 14 (71 %) vs. 18 / 51 (35 %), p = 0.02. CONCLUSIONS: Compromised postprocedural infrapopliteal run-off predisposes to early restenosis/reocclusion after femoropopliteal PTA. Deterioration of infrapopliteal run-off in the year after femoropopliteal PTA is accompanied by worsening of long-term femoropopliteal patency.

Antiplatelet and antithrombotic treatment of patients with peripheral arterial disease.

Platelets and coagulation system play a pivotal part in the progression of peripheral arterial disease (PAD) and the genesis of complications. Therefore, antiplatelet and antithrombotic drugs represent one of the basic options for prevention and the treatment in such patients. As the data on the efficacy of these drugs in PAD patients are limited and contradictory, authors prepared an overview of the literature and recommendations for the use of these drugs. Antiplatelet therapy significantly reduces the incidence of death and cardiovascular events and prevents progression of local disease in PAD patients. Aspirin represents the first-line of antiplatelet drugs. Low-dose aspirin (75-325 mg) is as effective as higher doses. However, higher doses of aspirin result in increased risk of gastrointestinal (GI) bleeding and very low-doses (<75 mg) are less effective. Clopidogrel is used in place of low-dose aspirin in patients who have aspirin-related intolerance or allergy. Combined antiplatelet therapy is slightly more effective than aspirin alone only in patients with a history of established vascular disease. Oral anticoagulant therapy alone or in combination with aspirin was in PAD patients not shown to be more effective than aspirin alone in prevention of cardiovascular events, but is probably more effective in prevention of graft occlusion. However the combination is related to an increased risk of bleeding. Moderate intensity of warfarin treatment would be acceptable in the presence of coexisting indications such as atrial fibrillation or recent venous thrombosis.

Does the preventive effect of different drugs depend on location of the atherosclerotic process?

Atherosclerosis can affect nearly any part of the arterial system. Therefore, it is considered as a generalized disease. As most probably similar or identical etiopathogenetic mechanisms are involved in different atherosclerotic diseases, a different effect of treatment of risk factors on atherosclerotic lesions in different parts of the vascular system is expected. Until now, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been devoted to the management of cerebrovascular and much less to peripheral arterial disease, despite their significant morbidity and mortality. The data from recent trials have indicated that treatment of patients with antiplatelet drugs, statins, antihypertensive and antidiabetic drugs prevents the progression of coronary atherosclerosis, reduces cardiovascular events and improves prognosis of coronary patients. Subgroup analyses from large studies have also shown that treatment of risk factors for atherosclerosis with drugs reduces cardiovascular events and improves prognosis of cerebrovascular and peripheral arterial occlusive disease. Although some studies indicate that the effects of distinct preventive procedures are to some extent dependent on the locations of atherosclerotic disease, it seems that the success of preventive measures is mostly related to the progression of the disease or the risk of treated population and not on the treated vascular bed.

The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis.

During the last decade, the role of inflammation in the etiopathogenesis of arterial thrombosis has been elucidated. However, little is known about the relationship between inflammation and venous thrombosis. Recently, inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins. The data indicate that inflammation of the vessel wall initiates thrombus formation in an intact vein and that inflammation and coagulation systems are coupled by a common activation pathway. The first event in thrombus formation is most probably activation of endothelial cells, platelets and leucocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system through the induction of a tissue factor. Therefore, the key event in the initiation of venous thrombus formation is most probably vein wall inflammation. However, expected relationship between inflammatory markers as indicators of inflammatory process and clinical venous thromboembolism (VTE) has not yet been elucidated. C-reactive protein does not appear to be useful in predicting future venous thrombosis or to be useful in the diagnosis of VTE. Recently, it was demonstrated that probable association between VTE and several other markers of inflammation such as: interleukin (IL)-6, IL-8 and tumor necrosis factor-a exists. While these markers of inflammation were studied during or after acute venous thrombosis, further prospective studies are needed to determine the predictive value of inflammatory markers for VTE. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy. That inflammation is the basic etiopathogenetic process of VTE is also supported by the relation of some risk factors to both arterial and venous thrombosis: age, increased body mass index, hypercholesterolemia, hypertension, lupus anticoagulant and hyperhomocysteinemia. A relation was also found between preclinical and clinical atherosclerotic disease and VTE. Also in line with these arguments are the preventive effects of aspirin and statins in both arterial and venous disease.