Atherosclerosis in systemic lupus erythematosus

Cardiovascular disease (CVD), comprising coronary heart disease and stroke, is one of the most important causes of death in patients with systemic lupus erythematosus (SLE). The risks of developing both clinical CVD and sub-clinical atherosclerosis are increased in patients with SLE. This increase is not fully explained by traditional cardiovascular risk factors such as smoking, hypertension and elevated cholesterol, and it is believed that immune dysfunction also contributes to CVD risk in SLE. In particular, recent studies have shown that abnormalities in both serum lipid profile and the autoantibody and T lymphocyte response to lipids may play a role in development of atherosclerosis. The standard CVD risk calculation algorithms based on traditional risk factors underestimate the risk of developing CVD in patients with SLE. Thus, novel algorithms incorporating new biomarkers such as pro-inflammatory high-density lipoprotein and use of imaging techniques such as carotid ultrasound scanning may become increasingly valuable

IgG anti-apolipoprotein A-1 antibodies in patients with systemic lupus erythematosus are associated with disease activity and corticosteroid therapy: an observational study.

IgG anti-apolipoprotein A-1 (IgG anti-apoA-1) antibodies are present in patients with systemic lupus erythematosus (SLE) and may link inflammatory disease activity and the increased risk of developing atherosclerosis and cardiovascular disease (CVD) in these patients. We carried out a rigorous analysis of the associations between IgG anti-apoA-1 levels and disease activity, drug therapy, serology, damage, mortality and CVD events in a large British SLE cohort

Studies of serology and vascular ultrasound in patients with systemic lupus erythematosus - focus on cardiovascular disease

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease characterised by the presence of autoantibodies. Active inflammation in patients with SLE can cause clinical effects in various organs and serum biomarkers can be helpful in monitoring the disease. Over time, patients with SLE have an increased risk of developing atherosclerosis. This risk is partially due to standard risk factors such as smoking and hypertension, but also due to SLE-specific immunological factors. In this thesis I have studied three linked questions; 1) Systemic inflammation can lead to endothelial activation and increased release of nitric oxide. This leads to nitration of serum proteins. Using capture ELISA, I studied levels of nitrated nuclesosomes and nitrated albumin in patients with SLE. Nitrated nucleosome levels were higher in patients with SLE than controls, and were related to some forms of disease activity notably in the central nervous system, but not atherosclerosis. 2) High-density lipoprotein (HDL) and its main structural component, apolipoprotein A1 (ApoA1), have an atheroprotective role. Using direct ELISA, I measured serum levels of anti-ApoA1 and anti-HDL antibodies in patients with SLE. IgG anti-apoA1 levels were associated with increased disease activity and with drug treatment, but not with atherosclerosis. 3) Previous authors used vascular ultrasound to demonstrate asymptomatic carotid plaque in between 30% and 40% of patients with SLE. I used new, more sensitive measures of carotid and femoral atherosclerosis in 100 patients with no previous history of CVD to investigate the factors associated with presence, area, volume and echogenicity of plaque. Thirty-six patients had plaque. Intima–media thickness (IMT) was associated with age and disease duration but not activity. Total plaque area (TPA), however, was increased in patients with persistently active disease and also with anti-HDL levels. Lipid profile was associated with both IMT and TPA. Plaque echogenicity was associated with disease activity and renal function. Comparison of these 100 SLE patients with an age/sex matched control group showed significant differences in morphology and echogenicity of plaque

A direct kinematical derivation of the relativistic Sagnac effect for light or matter beams

The Sagnac time delay and the corresponding Sagnac phase shift, for relativistic matter and electromagnetic beams counter-propagating in a rotating interferometer, are deduced on the ground of relativistic kinematics. This purely kinematical approach allows to explain the ''universality'' of the effect, namely the fact that the Sagnac time difference does not depend on the physical nature of the interfering beams. The only prime requirement is that the counter-propagating beams have the same velocity with respect to any Einstein synchronized local co-moving inertial frame.Comment: 10 pages, 1 EPS figure, to appear in General Relativity and Gravitatio

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease. Standard serum lipid measurements in clinical practice do not predict cardiovascular disease risk in patients with SLE. More detailed analysis of lipoprotein taxonomy could identify better predictors of cardiovascular disease risk in SLE. Approach and Results: Eighty women with SLE and no history of cardiovascular disease underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (patients with SLE with subclinical plaque) and 50 had no plaques (patients with SLE with no subclinical plaque). Serum samples obtained at the time of the scan were analyzed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data were analyzed using logistic regression and 5 binary classification models with 10-fold cross validation. Patients with SLE had global changes in complex lipoprotein profiles compared with healthy controls despite having clinical serum lipid levels within normal ranges. In the SLE cohort, univariate logistic regression identified 4 metabolites associated with subclinical plaque; 3 subclasses of VLDL (very low-density lipoprotein; free cholesterol in medium and large VLDL particles and phospholipids in chylomicrons and extremely large VLDL particles) and leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque groups with the greatest accuracy (0.800). Notably, free cholesterol in large VLDL particles and age differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque in all models. CONCLUSIONS: Serum metabolites are promising biomarkers to uncover and predict multimetabolic phenotypes of subclinical atherosclerosis in SLE

Using serum metabolomics analysis to predict sub-clinical atherosclerosis in patients with SLE

Background: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease (CVD) and 30-40% have sub-clinical atherosclerosis on vascular ultrasound scanning. Standard measurements of serum lipids in clinical practice do not predict CVD risk in patients with SLE. We hypothesise that more detailed analysis of lipoprotein taxonomy could identify better predictors of CVD risk in SLE. / Methods: Eighty patients with SLE and no history of CVD underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (SLE-P) and 50 had no plaques (SLE-NP). Serum samples obtained at the time of the scan were analysed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data was analysed using logistic regression and five binary classification models with 10-fold cross validation; decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. / Results: Univariate logistic regression identified four metabolites associated with the presence of sub-clinical plaque; three subclasses of very low density lipoprotein (VLDL) (percentage of free cholesterol in medium and large VLDL particles and percentage of phospholipids in chylomicrons and extremely large VLDL particles) and Leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between SLE-P and SLE-NP with greatest accuracy (0.800). Notably, percentage of free cholesterol in large VLDL particles and age were identified by all models as being important to differentiate between SLE-P and SLE-NP patients. / Conclusion: Serum metabolites are a promising biomarker for prediction of sub-clinical atherosclerosis development in SLE patients and could provide novel insight into mechanisms of early atherosclerosis development

The Sagnac Phase Shift suggested by the Aharonov-Bohm effect for relativistic matter beams

The phase shift due to the Sagnac Effect, for relativistic matter beams counter-propagating in a rotating interferometer, is deduced on the bases of a a formal analogy with the the Aharonov-Bohm effect. A procedure outlined by Sakurai, in which non relativistic quantum mechanics and newtonian physics appear together with some intrinsically relativistic elements, is generalized to a fully relativistic context, using the Cattaneo's splitting technique. This approach leads to an exact derivation, in a self-consistently relativistic way, of the Sagnac effect. Sakurai's result is recovered in the first order approximation.Comment: 18 pages, LaTeX, 2 EPS figures. To appear in General Relativity and Gravitatio

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque

Accelerated atherosclerosis is a complication of the autoimmune rheumatic disease systemic lupus erythematosus (SLE). We questioned the role played by invariant natural killer T (iNKT) cells in this process because they not only are defective in autoimmunity but also promote atherosclerosis in response to CD1d-mediated lipid antigen presentation. iNKT cells from SLE patients with asymptomatic plaque (SLE-P) had increased proliferation and interleukin-4 production compared with those from SLE patients with no plaque. The anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes but not B cells. Healthy iNKT cells differentiated in the presence of healthy monocytes and SLE-P serum polarized macrophages toward an anti-inflammatory M2 phenotype. Conversely, patients with clinical cardiovascular disease had unresponsive iNKT cells and increased proinflammatory monocytes. iNKT cell function could link immune responses, lipids, and cardiovascular disease in SLE patients and, together with serum lipid taxonomy, help predict preclinical atherosclerosis in SLE patients

The relativistic Sagnac Effect: two derivations

The phase shift due to the Sagnac Effect, for relativistic matter and electromagnetic beams, counter-propagating in a rotating interferometer, is deduced using two different approaches. From one hand, we show that the relativistic law of velocity addition leads to the well known Sagnac time difference, which is the same independently of the physical nature of the interfering beams, evidencing in this way the universality of the effect. Another derivation is based on a formal analogy with the phase shift induced by the magnetic potential for charged particles travelling in a region where a constant vector potential is present: this is the so called Aharonov-Bohm effect. Both derivations are carried out in a fully relativistic context, using a suitable 1+3 splitting that allows us to recognize and define the space where electromagnetic and matter waves propagate: this is an extended 3-space, which we call "relative space". It is recognized as the only space having an actual physical meaning from an operational point of view, and it is identified as the 'physical space of the rotating platform': the geometry of this space turns out to be non Euclidean, according to Einstein's early intuition.Comment: 49 pages, LaTeX, 3 EPS figures. Revised (final) version, minor corrections; to appear in "Relativity in Rotating Frames", ed. G. Rizzi and M.L. Ruggiero, Kluwer Academic Publishers, Dordrecht, (2003). See also http://digilander.libero.it/solciclo

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study.

BACKGROUND: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. METHODS: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. RESULTS: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. CONCLUSIONS: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE