Harald Froehlich

Neutrophil-to-lymphocyte ratio and its association with critical limb ischemia in PAOD patients.

Background The Neutrophil-to-Lymphocyte ratio (NLR) is an easy to perform test from the white blood cell count. An increase in NLR has been associated with vascular endpoints reflecting inflammation in atherosclerotic lesions. Atherosclerosis is a global threat and vascular endpoints, like myocardial infarction or critical limb ischemia (CLI), are a leading cause of death in industrialized countries. We therefore investigated NLR and its association with CLI and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. Methods and Findings We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. NLR was calculated and the cohort was divided into tertiles according to the NLR. An optimal cut-off value for the continuous NLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in NLR. As an optimal cut-off a NLR of 3.95 was identified. Two groups were categorized, one containing 1441 patients (NLR≤3.95) and a second group with 680 patients (NLR>3.95). CLI was more frequent in NLR>3.95 patients (330(48.5%)) compared to NLR≤3.95 patients (350(24.3%)) (p<0.001), as were prior myocardial infarction (48(7.0%) vs. 47(3.3%), p<0.001) and stroke (73(10.7) vs. 98(6.8%), p<0.001). Regarding other inflammatory parameters, C-reactive protein (median 5.6 mg/l (2.3–19.1) vs. median 3 mg/l (1.5–5.5)) and fibrinogen (median 412 mg/dl (345.5–507.5) vs. 344 mg/dl (308–403.5)) also significantly differed in the two patient groups (both p<0.001). A NLR>3.95 was associated with an OR of 2.5 (95%CI 2.3–2.7) for CLI even after adjustment for other vascular risk factors. Conclusions An increased NLR is significantly associated with patients at high risk for CLI and other vascular endpoints. The NLR is an easy to perform test, which could be used to highlight patients at high risk for vascular endpoints.

Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis.

Objective Endothelial dysfunction plays a key role in the development, progression, and clinical manifestation of atherosclerosis, and in symptomatic peripheral arterial disease, endothelial dysfunction and enlarged intima-media thickness might be associated with increased cardiovascular risk. Flow-mediated dilatation and serologic parameters are used to evaluate individual endothelial function. Brachial intima-media thickness, a less recognized parameter of cardiovascular risk, is independently associated with coronary artery disease. The aim of this study was to evaluate the prognostic value of ultrasound and serologic parameters of endothelial function in relation to cardiovascular mortality in peripheral arterial disease. Design monocentric, prospective cohort study. Methods Flow mediated dilatation and brachial intima-media thickness were assessed in 184 (124 male) patients with peripheral arterial disease (Rutherford stages 2–3). Serologic parameters of endothelial function included asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine. Cardiovascular events were recorded during a follow-up of 99.1±11.1 months. Subjects who died of noncardiovascular causes were excluded from further analysis. Results Eighty-two patients (44.6%) died during follow-up after a mean duration of 49.7±28.3 months. There were 49 cardiovascular deaths (59.8%) and 33 other deaths (40.2%). Flow mediated dilatation was associated with cardiovascular death [1.17% (0.0, 4.3) vs. 4.1% (1.2, 6.4), p<0.001]. Intima-media thickness was greater in patients who succumbed to cardiovascular disease [0.37 mm (0.30, 0.41)] than in survivors [0.21 mm (0.15, 0.38), p<0.001]. Brachial intima-media thickness above 0.345 mm was most predictive of cardiovascular death, with sensitivity and specificity values of 0.714 and 0.657, respectively (p<0.001). Furthermore, ADMA levels above 0.745 µmol/l and SDMA levels above 0.825 µmol/l were significantly associated with cardiovascular death (p<0.001 and 0.030). Conclusion In symptomatic peripheral arterial disease, decreased flow mediated dilatation, enlarged intima-media thickness, and elevated levels of ADMA and SDMA were associated with increased cardiovascular risk.

Asymptomatic deep vein thrombosis and superficial vein thrombosis in ambulatory cancer patients: impact on short-term survival

Background:Asymptomatic venous thrombotic events (VTEs) are possible findings in ambulatory cancer patients. Data regarding the incidence and clinical impact of asymptomatic VTEs are conflicting. We therefore conducted a study to evaluate the occurrence of asymptomatic VTEs of the lower limbs in ambulatory cancer patients to further evaluate the association of these asymptomatic VTEs on survival during a 9-month follow-up period.Methods:In our prospective cohort, we included 150 consecutive ambulatory cancer patients who were free of any clinical symptoms for VTEs. Compression ultrasound to detect deep vein thrombosis (DVT) and superficial venous thrombosis (SVT) of the lower limbs was performed by a vascular specialist in all patients at baseline. In case of pathological findings the patients were treated with low molecular weight heparin (LMWH) because of current established guidelines. The occurrence of death was investigated during a 9-month follow-up period.Results:A total of 27 (18%) patients with VTEs were detected, which included 13 patients (8.7%) with a SVT and 16 patients (10.7%) showing a DVT. Two patients had both, a SVT and a DVT as well. During the 9-month follow-up period the occurrence of a VTE at baseline was associated with a 2.4-fold increased risk for death (HR 2.4 (1.2–5.3); P=0.03).Conclusion:Asymptomatic VTEs of the lower limbs in ambulatory cancer patients are frequently occurring concomitant features and are associated with poor survival during a 9-month follow-up period despite anticoagulation with LMWH.

Intra-arterial injection, a rare but serious complication of sclerotherapy

Intra-arterial injections represent the most feared complication of sclerotherapy for varicose veins. We present a case of an inadvertent intra-arterial injection of polidocanol at the left medial calf in a 59-year-old woman with subsequent arterial occlusions of the posterior tibial artery and foot arteries. Despite several therapeutic interventions, lower-limb amputation could not be prevented. We conducted a PubMed search for articles reporting arterial complications related to sclerotherapy, in order to evaluate aetiology, clinical presentation, therapeutic management and outcome of sclerotherapy-associated intra-arterial injections during the past 50 years. Intra-arterial injection of a sclerosing solution was reported in 63 cases, mostly after injection near the ankle region or the distal medial calf. Clinical presentation was frequently characterized by immediate pain during injection and distal ischaemia with subsequent tissue loss. Despite several treatment approaches, amputation could not be prevented in 31 cases (52.5%). The pathophysiology of arterial complications related to intra-arterial injection and advisable therapeutic interventions are discussed. Inadvertent intra-arterial injection represents a limb-threatening complication of sclerotherapy. Target-oriented and prompt therapy seems inevitable in order to reduce the risk of permanent tissue loss and amputation.

Endothelial function and carotid intima-media thickness in giant-cell arteritis.

Vascular endothelial dysfunction and intima‐media thickness are characteristic aspects of several vasculitides. We investigated retrospectively the impact of steroid treatment on endothelial dysfunction and intima‐media thickness in giant‐cell arteritis.

High factor VIII activity, high plasminogen activator inhibitor 1 antigen levels and low factor XII activity contribute to a thrombophilic tendency in elderly venous thromboembolism patients.

affect the fibrinolytic capacity and increases the risk of thrombotic events in the arterial system. One of the primary regulators of the fibrinolytic system is plasminogen activator inhibitor 1 (PAI 1). Overexpression of PAI 1 may lead to impaired activity of the fibrinolytic system [19] . The aim of our study was to evaluate the age-related differences in activity of clotting factors VIII, XI and XII in patients with a first episode of VTE as well as differences in the fibrinolytic system of these patients reflected by PAI 1 antigen levels. We further evaluated the difference in natural anticoagulants AT, Pro C and Pro S between our older and younger patients. Patients with a history of a single episode of VTE in the past 2 years were enrolled over a period of 6 months at the outpatient clinic of the Division of Angiology, Medical University Graz, Austria. As this was supposed to be a pilot study, no sample size calculation was performed. We excluded patients on full-dose warfarin, patients with active malignancies, patients with acute inflammation, patients with a positive test for antiphospholipid antibodies and patients with signs of an acute deep vein thrombosis, as all these entities influence the activity of clotting Age is an independent risk factor for venous thromboembolic events (VTE) [1] . This seems to be a multifactorial phenomenon. Older patients are at higher risk for VTE due to an increase in disability [2] . Furthermore, the plasma concentration of several clotting factors increases with age in healthy humans as a physiological ageing process [3–7] . These changes in clotting factor activity in the elderly are supposed to be in balance with an increase in natural anticoagulants such as antithrombin (AT), protein C (Pro C) and protein S (Pro S) [8] . Factor VIII, a cofactor in the activation of factor X, is a clotting factor which increases with age, reaching a mean of 1 200 IU/dl in the 7th decade of life [3, 9] . High factor VIII levels are associated with venous as well as with arterial vascular events [10–13] . Changes in the activity of clotting factors XI and XII are also proposed as thrombophilic risk factors [14–16] . However, age-dependent differences in activity of these 2 clotting factors have not yet been described in the literature so far, although they could be of clinical interest. Factor XII activates the fibrinolytic system directly or indirectly and inhibits the thrombin-induced platelet activation [17, 18] . Therefore, low factor XII activity should Received: July 19, 2010 Accepted after revision: September 8, 2010 Published online: November 12, 2010

Simvastatin Efficiently Lowers Small LDL-IgG Immune Complex Levels: A Therapeutic Quality beyond the Lipid-Lowering Effect

We investigated a polyethylene glycol non-precipitable low-density lipoprotein (LDL) subfraction targeted by IgG and the influence of statin therapy on plasma levels of these small LDL-IgG-immune complexes (LDL-IgG-IC). LDL-subfractions were isolated from 6 atherosclerotic subjects and 3 healthy individuals utilizing iodixanol density gradient ultracentrifugation. Cholesterol, apoB and malondialdehyde (MDA) levels were determined in each fraction by enzymatic testing, dissociation-enhanced lanthanide fluorescence immunoassay and high-performance liquid chromatography, respectively. The levels of LDL-IgG-IC were quantified densitometrically following lipid electrophoresis, particle size distribution was assessed with dynamic light scattering and size exclusion chromatography. The influence of simvastatin (40 mg/day for three months) on small LDL-IgG-IC levels and their distribution among LDL-subfractions (salt gradient separation) were investigated in 11 patients with confirmed coronary artery disease (CAD). We demonstrate that the investigated LDL-IgG-IC are small particles present in atherosclerotic patients and healthy subjects. In vitro assembly of LDL-IgG-IC resulted in particle density shifts indicating a composition of one single molecule of IgG per LDL particle. Normalization on cholesterol levels revealed MDA values twice as high for LDL-subfractions rich in small LDL-IgG-IC if compared to dominant LDL-subfractions. Reactivity of affinity purified small LDL-IgG-IC to monoclonal antibody OB/04 indicates a high degree of modified apoB and oxidative modification. Simvastatin therapy studied in the CAD patients significantly lowered LDL levels and to an even higher extent, small LDL-IgG-IC levels without affecting their distribution. In conclusion simvastatin lowers levels of small LDL-IgG-IC more effectively than LDL-cholesterol and LDL-apoB levels in atherosclerotic patients. This antiatherogenic effect may additionally contribute to the known beneficial effects of this drug in the treatment of atherosclerosis.

Unusual deep vein thrombosis sites: magnetic resonance venography in patients with negative compression ultrasound and symptomatic pulmonary embolism

Objectives To evaluate the clinical characteristics of patients with pulmonary embolism (PE), negative compression ultrasound (CUS) of the lower limbs and detection of unusual deep vein thrombosis (DVT) sites by means of magnetic resonance (MR) venography. Methods A retrospective data analysis of PE patients hospitalized at our institution from April 2009 to 2011. Results From April 2009 to 2011, a total of 762 PE patients were treated at our institution. In 169 of these patients CUS for DVT was negative. In these patients MR venography was performed for further evaluation. We found venous thrombosis at unusual sites in 12 of these patients. Due to free floating thrombus masses and fear of life-threatening PE progression we inserted an inferior vena cava filter in three of these 12 patients. The leading venous thromboembolism risk factor in our patients was immobilization (5 patients, 41.7%). Conclusions We conclude that especially in patients with PE and negative CUS of the lower limbs a thrombosis of the pelvic veins should be considered in case of symptoms for venous thrombosis in this area. Further diagnostic work-up with MR venography should be scheduled in these patients especially in patients with risk factor immobilization as therapeutic consequences might occur.