Oxidized low-density lipoprotein as a risk factor of thrombosis in antiphospholipid syndrome

Beta2-Glycoprotein I (beta2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome (APS). We recently reported that oxidized LDL(oxLDL) is subsequently targeted by beta2-GPI and anti-beta2-GPI auto-Abs and that-carboxyl variants of 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) octadodecanoate (oxLig-2), are ligands for beta2-GPI (J Lipid Re 2001; 42: 697; J Lipid Res 2002; 43: 1486). These beta2-GPI ligands provide an electrostatic interaction between oxLDL and beta2-GPI followed by forming stable complexes (such as Schiff base adducts). The omega-carboxyl function in these ligand is responsible for beta2-GPI binding to oxLDL and the oxLDL-beta2-GPI complexes are anti-beta2-GPI auto-Ab-dependently taken up by macrophages (i.e., by phagocytosis). Our recent observations are consistent with the evidence that beta2-GPI co-localizes with lymphocytes and mononuclear cells in human athero-plaques. Thus, autoimmune thrombogenesis (atherogenesis) is linked to interaction of anti-beta2-GPI Abs with the beta2-GPI-oxLDL complexes. We propose an alternative idea, that an immune response against the beta2-GPI-oxLDL complexes may be involved in mechanisms in the development of atherosclerosis, which has been explained by the theory of 'the response to injury'.     

Presence of antiphospholipid antibody is a risk factor in thrombotic events in patients with antiphospholipid syndrome or relevant diseases

Antiphospholipid antibodies (aPL) including lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG and aCL-β2-glycoprotein I (β2GPI) complex IG are causative factors for thrombotic event (THE). We retrospectively investigated relationships between aPLs and THE in 458 patients suspected of having antiphospholipid syndrome. THEs were observed in 232 of 458 patients, including 148 cases of venous thrombosis, 59 of arterial thrombosis, 18 of microthrombosis, and 20 of complications of pregnancy. The frequency of THE was significantly high in patients positive for LA and/or aPL. In patients with autoimmune disease (AID), the frequency of THE was significantly high in patients with any types of aPLs. Additionally, risk of THE was significantly increased in patients with more than two types of aPLs. Prolonged activated partial thromboplastin time indicated a high risk for THE. However, neither thrombocytopenia nor AID was a risk for THE. In conclusion, the presence of aPL is an indicator for high risk of THE in patients in whom THE was suspected. However, the risk of THE in aPL-positive patients varied among patients with different underlying diseases.     

CNS dysfunction in the antiphospholipid syndrome

Though many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in this disease. We review clinical data obtained from a large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white matter disease and behavioral changes in APS or linked to laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with beta2-glycoprotein I, a central autoantigen in APS, which induces persistent high levels of aPL. These mice develop hyperactive behavior after a period of four to five months as well as deficits in learning and memory and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. Another model we have developed, in which IgG from APS patients induce depolarization of brain synaptoneurosomes, may serve as a model for the pathogenesis of epilepsy in APS.     

Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome

The objective of this study was to assess the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (PAPS). We studied 28 patients with SLE, 10 patients with PAPS, and 24 healthy controls. VEGF plasma levels were measured by ELISA. Immunolocalization of VEGF was done in renal tissue from SLE patients and cadaveric controls. Our results showed that VEGF plasma levels were increased in SLE patients compared with PAPS and controls. The correlation between clinical manifestations and VEGF levels revealed that SLE patients with renal failure had significantly increased plasma VEGF levels (134.1 + 91.0 pg/ml) compared with SLE patients with normal renal function (42.9 + 19.0 pg/ml), PAPS patients (41.9 + 26.6 pg/ml), and controls (36.2 + 27.0 pg/ml; P < 0.01). Immunostaining showed a strong expression of VEGF in SLE renal tissue samples. Our preliminary results indicate that VEGF is increased in plasma from patients with lupus nephritis and a moderate degree of renal failure and is overexpressed in renal tissue from these patients.     

Remnant lipoproteinemia is a risk factor for endothelial vasomotor dysfunction and coronary artery disease in metabolic syndrome

This study aimed to determine whether elevated levels of remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, might be associated with coronary artery disease (CAD) and endothelial vasomotor dysfunction in metabolic syndrome. The fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 210 patients with metabolic syndrome meeting ATP III criteria. Flow-mediated endothelium-dependent dilatation (FMD) in the brachial artery during reactive hyperemia was examined by high-resolution ultrasound technique. This study found that elevated RLP-C levels were a significant and independent risk factor for impaired FMD and angiographically proven coronary artery disease (CAD). Treatment with bezafibrate (n = 20) or atorvastatin (n = 20) for 4 weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. The % reduction in RLP-C levels from baseline after the treatment was independently correlated with the magnitude of improvement in FMD after adjustment for the % changes in levels of triglyceride, hsCRP, and IL-6, and HOMA index. Thus, elevated levels of RLP-C are a risk factor for CAD and endothelial vasomotor dysfunction, a predictor of coronary events, in metabolic syndrome. Measurement of RLP-C is useful for assessment of CAD risk and therapeutic effects in metabolic syndrome.     

Cardiac dysfunction in patients with systemic lupus erythematosus and antiphospholipid syndrome

OBJECTIVE: To comparatively assess the parameters of systolic and diastolic cardiac function in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: Consecutive patients (n=74) who were free of cardiovascular symptoms were divided into four groups: (1) SLE (n=23); (2) SLE with antiphospholipid antibodies (aPL; n=18); (3) SLE with APS (n=20); and (4) primary antiphospholipid syndrome (PAPS; n=13). Pulsed, continuous, colour Doppler echocardiography, and M-mode and B-mode studies were performed. RESULTS: Left ventricular end diastolic and end systolic dimensions were higher in SLE as compared with patients with PAPS (p=0.022 and 0.022, respectively), with a trend towards a lower fractional shortening in SLE (p=0.07), suggesting systolic dysfunction. Parameters of diastolic function were more impaired in patients with APS, reflected by lower left ventricular and right ventricular E wave to A wave (E:A) ratios in patients with APS (groups 3, 4) compared with those without APS (groups 1, 2; 1.15 (0.40) v 1.49 (0.43), p=0.001 and 1.19 (0.31) v 1.49 (0.41), p=0.001, respectively) and a more prolonged left ventricular isovolumic relaxation time (IVRT; 94.2 (24.6) v 84.4 (17) ms, respectively, p=0.055). Patients with APS were older than those without APS (47.12 (14.86) v 34.29 (12.6), p=0.0001). Patients with SLE were younger than those with PAPS (38.19 (14.68) v 48.53 (13.97), p=0.023). CONCLUSION: Abnormal echocardiographic findings were detected frequently in asymptomatic patients with SLE or PAPS. Although patients with SLE were younger, left ventricular systolic function was more impaired in patients with SLE compared with those with PAPS, whereas left ventricular and right ventricular diastolic function, as reflected by IVRT and E:A ratios, were significantly more impaired in patients with APS.     

Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus

OBJECTIVE: The premature atherosclerosis seen in patients with systemic lupus erythematosus (SLE) is not explained by traditional risk factors. SLE disease activity, such as renal involvement and presence of autoantibodies, is associated with elevated serum levels of type I interferon (IFN-I), a family of cytokines with potent antiviral and antiproliferative effects. This study was undertaken to test the hypothesis that elevated IFN-I levels could lead to endothelial dysfunction, a surrogate for cardiovascular disease, by causing a reduction in the number of endothelial progenitor cells (EPCs), bone marrow-derived cells that participate in endothelial repair. METHODS: EPCs were enumerated in the peripheral blood of SLE patients (n = 70) and healthy controls (n = 31), using a colony-forming assay. Serum IFN-I levels were quantified by real-time polymerase chain reaction measurement of the expression of the IFN-I-inducible gene MX1. Endothelial function was determined by peripheral arterial plethysmography. RESULTS: SLE patients had markedly reduced levels of EPC colony-forming units compared with controls (median 5.7/ml peripheral blood [interquartile range 1.9-12.8] versus 28.5/ml peripheral blood [14.7-47.3]; P < 0.0001), and the depletion of EPCs was more dramatic in patients with elevated levels of IFN-I. Stepwise multiple regression analysis showed that MX1 expression and serum levels of C-reactive protein were independently associated with the reduction of EPCs. Importantly, high IFN-I levels were associated with impaired endothelial function in patients with SLE. CONCLUSION: These data support the novel hypothesis that depletion of EPCs caused by excessive IFN-I may be linked to endothelial dysfunction and increased cardiovascular risk in SLE.     

Activation of endothelial cells by antiphospholipid antibodies--a possible mechanism triggering thrombosis in patients with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an antibody-mediated hypercoagulable state characterized by recurrent venous and arterial thromboembolic events. The presence of serum antibodies are collectively termed as antiphospholipid antibodies (aPL) and is the hallmark of the disease. Interest in the pathogenesis has mostly been focused on the blood coagulation factor. However, endothelial cells might play an important role. When stimulated, cell membrane would flip to expose negatively charged phospholipids and activation markers such as adhesive molecules may appear. We consider that these changes may play an important role in the initiation of the thrombotic process when endothelial cells encounter a PL. In this study, we incubated human umbilical vein endothelial cells (HUVECs) with IgG isolated from patients with APS and found that the HUVECs were activated by the expression of negatively charged phospholipids, as shown by high annexin V binding and negative propidium iodide staining and by an increase in the level of intracellular cell adhesion molecule-1 on the cell surface. The above findings indicate that endothelial cells can be activated on exposure to aPL and trigger the thrombotic event.     

Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome

OBJECTIVE: To evaluate the prevalence of diastolic dysfunction in patients with anticardiolipin antibodies (aCL) and to examine whether the antiphospholipid syndrome (APS) is associated with diastolic dysfunction independently of valvular abnormalities and systolic dysfunction. METHODS: Pulsed, continuous, colour Doppler echocardiography was performed in 179 subjects, of whom 15 were excluded from the analysis because of systolic dysfunction or severe valvular disease. The remaining 164 subjects included 29 patients with primary APS, 26 patients with secondary APS (APS in the presence of systemic lupus erythematosus (SLE)), and 30 patients with SLE and aCL but without APS; 43 patients with SLE without aCL and 36 normal volunteers served as control groups. RESULTS: The groups compared differed significantly in all measures of right ventricular function. There was a gradation of increasing diastolic function impairment as manifested by prolonged deceleration time (DT) and isovolumic relaxation time (IVRT) across the groups of patients with SLE without aCL, SLE with aCL, secondary APS, and primary APS. Differences in left ventricular diastolic function measures were less prominent. In regression analysis, DT increased by 19.6 ms (p=0.002) in the presence of primary APS and by 20.1 ms (p=0.038) in the presence of pulmonary hypertension. The titre of IgG aCL was the strongest predictor of a prolonged IVRT. CONCLUSION: Diastolic dysfunction, in particular of the right ventricle-that is, independent of valvular disease and systolic dysfunction, is a prominent feature of APS and may be related to the pathogenesis of the syndrome.     

Tissue factor in the antiphospholipid syndrome

Antiphospholipid (aPL) antibodies are clinically important acquired risk factors for thrombosis and pregnancy loss and are thought to have a direct prothrombotic effect in vivo. Data suggest that a major mechanism by which aPL antibodies contribute to thrombophilia is the upregulation of tissue factor (TF) (CD142) on blood cells and vascular endothelium. TF is the physiological trigger of normal blood coagulation and thrombosis in many hypercoagulable conditions. This article reviews the physiology of TF, the molecular regulation of TF expression and the effects of aPL antibodies on intravascular TF regulation and expression. Inhibition of TF and the pathways by which aPL antibodies induce TF expression are potentially attractive therapeutic targets in the antiphospholipid syndrome.     

Renal dysfunction as a cardiovascular risk factor

Indices of altered renal function (eg, microalbuminuria, increased serum creatinine concentration, or decrease in estimated creatinine clearance, particularly overt proteinuria) are independent predictors of cardiovascular morbidity and mortality. These parameters should be routinely evaluated in the elderly and in high cardiovascular risk populations, particularly when hypertension is present. Hypertensive kidney damage should be prevented by early aggressive treatment of hypertensive patients with microalbuminuria. To avoid further aggravation of high cardiovascular risk, antihypertensive agents devoid of unwanted metabolic side effects should be used. Epidemiologic information suggests that renal and cardiovascular outcome run parallel in this segment of the population.     

Anti-tissue factor pathway inhibitor activity in patients with primary antiphospholipid syndrome

The association between antiphospholipid antibodies and an increased risk of thrombosis in antiphospholipid syndrome (aPS) patients is probably caused by numerous mechanisms, including the effects of antibodies to phospholipid-binding proteins such as beta(2)-glycoprotein I and prothrombin. In this study, we investigated the inhibition of tissue factor pathway inhibitor (TFPI) in 33 patients with primary antiphospholipid syndrome (PAPS). TFPI was measured in PAPS patients using an amidolytic assay, dependent on the generation of activated factor X (Fxa), and this was compared with 55 healthy subjects. Functional levels of TFPI (mean +/- SD) were significantly lower in PAPS patients (0.89 +/- 0.37 U/ml) than the control group (1.05 +/- 0.15 U/ml) (P = 0.02). The difference was caused by a subset of five patients who had TFPI levels below the lower 99% confidence interval of the normal reference range, representing increased FXa generation in the assay system. IgG fractions were isolated from these five patients and five control subjects, then incorporated into normal plasma to measure FXa generation in the TFPI assay system. FXa generation was increased when polyclonal rabbit anti-human TFPI IgG (P < 0.0001) or PAPS IgG (P = 0.0001) were added to normal plasma, demonstrating inhibition of TFPI. The apparent anti-TFPI activity demonstrated in the five subjects with PAPS in this study may represent a significant new mechanism for thrombosis in patients with aPS, as it implies that increased tissue factor FVIIa-mediated thrombin generation might occur.     

Endothelial dysfunction in patients with antiphospholipid syndrome assessed with positron emission tomography.

BACKGROUND: There is limited knowledge about endothelial dysfunction in patients with primary antiphospholipid syndrome (PAPS). The purpose of this study was to evaluate endothelial function in patients with PAPS assessed by positron emission tomography. METHODS AND RESULTS: A 3-phase protocol--rest, cold pressor test (CPT), and adenosine positron emission tomography with nitrogen 13 ammonia--was used in 18 patients with PAPS and 18 healthy volunteers (HVs). Myocardial blood flow (MBF) was measured in each phase, with calculation of the endothelial-dependent vasodilation index, the increase in the MBF in response to CPT, and the myocardial flow reserve. An important trend was found in the myocardial flow reserve (2.76 +/- 1.04 in PAPS group vs 3.27 +/- 0.72 in HV group, P > .05), in the endothelial-dependent vasodilation index (1.19 +/- 0.31 in PAPS group vs 1.55 +/- 0.37 in HV group, P < .05), and in the percent change in the MBF in response to CPT (from rest) (19% +/- 31% in PAPS group vs 55% +/- 37% in HV group, P < .05). CONCLUSION: The CPT results obtained in this study showed that the PAPS patients studied have endothelial dysfunction.     

The time course of flow-mediated vasodilation and endothelial dysfunction in patients with a cardiovascular risk factor

The relationship between having a cardiovascular risk factor and endothelial dysfunction observed on a time-course analysis of brachial artery flow-mediated vasodilation (FMD) remains unclear. We enrolled 257 patients who had at least one cardiovascular risk factor. We measured FMD magnitude of the percentage change in peak diameter (ΔFMD), maximum FMD rate calculated as the maximum slope of dilation (FMD-MDR), and integrated FMD response calculated as the area under the dilation curve during the 60- and 120-second dilation periods (FMD-AUC₆₀ and FMD-AUC₁₂₀) using a semiautomatic edge-detection algorithm. FMD-AUC₆₀ and FMD-AUC₁₂₀ were negatively correlated with the Framingham risk score (FMD-AUC₆₀: r = ?0.15, P = .023; FMD-AUC₁₂₀: r = ?0.17, P = .007), whereas this association was not found in the case of either the ΔFMD or the FMR-MDR. The Framingham risk score was significantly higher in patients in the lowest tertile for FMD-AUC₁₂₀ (FMD-AUC₁₂₀ <5.0 mm × second) than in those in the highest tertile for FMD-AUC₁₂₀ (FMD-AUC₁₂₀ ≥11.0 mm × second) (12.9 ± 8.7 vs. 8.6 ± 7.8%, P = .002). The lowest tertile for FMD-AUC₁₂₀ was independently associated with the Framingham risk score (β = 0.10, P = .011), after adjustments were made for age, gender, and smoking and drinking status. FMD-AUC₁₂₀ was associated with cardiovascular risk.     

Disturbed sleep as risk factor for metabolic syndrome

Sleep disorders, sleep fragmentation, and chronically reduced sleep duration are increasingly common in western societies. In parallel, incidence of the metabolic syndrome and its key components, i.e. type 2 diabetes and obesity, is rapidly increasing. A huge number of epidemiological studies has shown a robust association between disturbed sleep quality, reduced sleep duration and the development of components of the metabolic syndrome. Moreover, there is growing evidence from experimental studies proving a causal link between sleep loss and disturbed human energy homeostasis. Short term sleep loss has been shown to reduce insulin sensitivity and glucose tolerance, increase feelings of hunger by modulating orexigenic/anorexigenic hormonal signaling, and disturb physical activity behavior. This review attempts to present an overview of the presently available literature on the link between sleep loss and disturbed human energy homeostasis, as well as on potential pathophysiological mechanisms.     

Subclinical thyroid dysfunction as a risk factor for cardiovascular disease

BACKGROUND: There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline). RESULTS: In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes. CONCLUSION: Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.