Prognostic value of urinary 11-dehydro-thromboxane B2 for mortality: A cohort study of stable coronary artery disease patients treated with aspirin.

AIM: There is a variable cardiovascular risk reduction attributable to aspirin because of individual differences in the suppression of thromboxane A2 and its downstream metabolite 11-dehydro-thromboxane B2 (11dhTxB2 ). The aim of this study is to evaluate the optimal cut point of urinary 11dhTxB2 for the risk of mortality in aspirin-treated coronary artery disease (CAD) patients. METHODS AND RESULTS: This was a prospective cohort study including stable CAD patients who visited the Baylor Heart and Vascular Hospital in Dallas or the Texas Heart Hospital Baylor Plano, TX between 2010 and 2013. The outcome of all-cause mortality was ascertained from chart review and automated sources. The 449 patients included in this analysis had a mean age of 66.1 ± 10.1 years. 67 (14.9%) patients died within 5 years; 56 (87.5%) of the 64 patients with known cause of death suffered a cardiovascular related mortality. Baseline ln(urinary 11dhTxB2 /creatinine) ranged between 5.8 and 11.1 (median = 7.2) with the higher concentrations among those who died (median: 7.6) than those who survived (median = 7.2, P < 0.001). Using baseline ln(11dhTxB2 ) to predict all-cause mortality, the area under the curve was 0.70 (95% CI: 0.64-0.76). The optimal cut point was found to be ln(7.38) = 1597.8 pg/mg, which had the following decision statistics: sensitivity = 0.67, specificity = 0.62, positive predictive value = 0.24, negative predictive value = 0.92, and accuracy = 0.63. CONCLUSION: Our data indicate the optimal cut point for urine 11dhTxB2 is 1597.8 (pg/mg) for the risk prediction of mortality over five years in stable patients with CAD patients treated with aspirin.

Is atherosclerosis an autoimmune disease?

Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds ß2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that ß2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-α Therapy.

OBJECTIVE: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with cardiovascular disease. The treatment of arthritis by tumor necrosis factor-α (TNF-α) inhibitors may decrease the serum concentrations of vascular biomarkers. We determined circulating levels of oxidized low-density lipoprotein (oxLDL)/ß2 glycoprotein I (ß2-GPI) complexes, antibodies to 60 kDa heat shock protein (anti-Hsp60), soluble urokinase plasminogen activator receptor (suPAR), and B-type natriuretic peptide (BNP) fragment in sera of RA and AS patients undergoing anti-TNF treatment. METHODS: Fifty-three patients with RA/AS were treated with etanercept or certolizumab pegol for 1 year. Circulating oxLDL/ß2-GPI complex (AtherOx), anti-Hsp60 IgG, and BNP8-29 fragment levels were assessed by ELISA. suPAR levels were determined by suPARnostic Quick Triage test. Flow-mediated vasodilation (FMD), carotid intima-media thickness (CIMT), and arterial pulse wave velocity (PWV) were determined by ultrasound. RESULTS: One-year anti-TNF treatment significantly decreased oxLDL/ß2-GPI levels, as well as suPAR levels in patients with critically high suPAR levels at baseline. In RA, BNP levels were higher in seropositive vs seronegative patients. Serum levels of these vascular biomarkers variably correlated with lipids, anticitrullinated protein antibodies, rheumatoid factor, and C-reactive protein. CIMT positively correlated with BNP, and PWV with suPAR and anti-Hsp60, whereas FMD inversely associated with anti-Hsp60. In repeated measures ANOVA analysis, disease activity supported the effects of anti-TNF treatment on 12-month changes in oxLDL/ß2-GPI. CIMT supported the effects of therapy on changes in anti-Hsp60 and suPAR. CONCLUSION: These biomarkers may be involved in the pathogenesis of atherosclerosis underlying RA/AS. TNF inhibition variably affects the serum levels of oxLDL/ß2-GPI, suPAR, and BNP.

Incisión de Spangaro en lesiones cardiacas penetrantes, reporte de casos.

INTRODUCCIÓN: El trauma en México es un problema mayor de salud pública, siendo una de las principales causas de mortalidad en personas jóvenes. La incidencia reportada de trauma cardiaco varía. El sitio primario de lesión miocárdica es la pared libre del ventrículo derecho. CASOS CLÍNICOS: Se reportan dos casos de pacientes lesionados con un instrumento punzocortante en el tórax, sufriendo lesión miocárdica que requirió tratamiento quirúrgico de urgencia. DISCUSIÓN: Existen diversas incisiones del tórax. La elección dependerá de la situación a tratar, el estado hemodinámico y el número de lesiones. Ante una lesión cardiaca, el abordaje de Spangaro es una prudente elección. INTRODUCTION: Trauma in Mexico is a major public health problem, being one of the main causes of mortality in young people. The reported incidence of cardiac trauma complications. The primary site of myocardial injury is the free wall of the right ventricle. CLINICAL CASES: Two cases of injured patients with a throbbing instrument in the chest are reported, suffering from myocardial injury that required emergency surgical treatment. DISCUSSION: There are various chest incisions. The choice will depend on the entity to be treated, the hemodynamic state, number of injuries. Faced with a heart injury, Spangaro's approach is a prudent choice.

Autoimmunity, infectious immunity, and atherosclerosis.

INTRODUCTION: Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease. DISCUSSION: We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry. CONCLUSION: Infectious cellular response may be proatherogenic,while the humoral response (antibody production) maybe protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.

Atherosclerosis in autoimmune diseases.

Lipid peroxidation occurs frequently in patients with systemic autoimmune diseases and contributes to autoimmune vascular inflammation. Oxidized low-density lipoprotein (oxLDL) interacts with beta2-glycoprotein I (beta2GPI), forming oxLDL/beta2GPI complexes. Circulating oxLDL/beta2GPI complexes and autoantibodies to these complexes have been demonstrated in patients with systemic lupus erythematosus and antiphospholipid syndrome. These findings suggest an immunogenic nature of the complexes and an active proatherogenic role in autoimmunity. Biochemical characterization of the complexes and immunohistochemical studies of atherosclerotic lesions suggest that most of the complexes originate in the arterial wall and are released into circulation. The in vitro macrophage uptake of oxLDL/beta2GPI complexes increased significantly in the presence of antiphospholipid antibodies (anti-beta2GPI), suggesting that macrophage Fcgamma receptors are involved in the lipid intracellular influx that leads to foam cell formation. These findings provide an immunologic explanation for the accelerated development of atherosclerosis seen in systemic lupus erythematosus and antiphospholipid syndrome.

Preventing autoimmune and infection triggered atherosclerosis for an enduring healthful lifestyle.

Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities (i.e., dyslipidemia), development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Experimental evidence from biochemical and clinical studies support the idea that arterial thrombosis is an autoimmune process resulting from 'autoantibody'-mediated pro-atherogenic mechanisms now seen in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). In addition, it has been shown that persistent infections of Chlamydia pneumoniae (C. pneumoniae), Porphyromonas gingivalis (P. gingivalis), and Helicobacter pylori (H. pylori) cause immune responses (infectious immunity) in their hosts that promote atherogenesis. In this article, we review recent progress in our understanding of immune- and infection-mediated atherosclerosis.

Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis.

Oxidized low-density lipoprotein (oxLDL) is thought to promote atherosclerosis through complex inflammatory and immunologic mechanisms that lead to lipid dysregulation and foam cell formation. Recent findings suggested that oxLDL forms complexes with beta2-glycoprotein I (beta2GPI) and/or C-reactive protein (CRP) in the intima of atherosclerotic lesions. Autoantibodies against oxLDL/beta2GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) and significantly correlate with arterial thrombosis. IgG autoantibodies having similar specificity emerged spontaneously in non-immunized NZWxBXSB F1 mice, an animal model of APS, and a monoclonal autoantibody (WB-CAL-1; IgG2a) against complexed beta2GPI (oxLDL/beta2GPI complexes) was derived from the same mice. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages. This observation strongly suggests that such IgG autoantibodies are pro-atherogenic. In contrast, IgM anti-oxLDL natural antibodies found in the atherosclerosis-prone mice (ApoE(-/-) and LDL-R(-/-) mice) have been proposed to be anti-atherogenic (protective). The presence of IgG anti-oxLDL antibodies in humans has been documented in many publications but their exact clinical significance remains unclear. In this article, we review recent progress in our understanding of the mechanisms involved in oxidation of LDL, formation of oxLDL complexes, and antibody mediated-immune regulation of atherogenesis.

Predictive Value of Oxidized Low-Density Lipoprotein/ß2-Glycoprotein-I Complexes (oxLDL/ß2GPI) in Nonautoimmune Atherothrombosis.

INTRODUCTION: Lipid oxidation is a definite feature of atherosclerosis, and oxidized low-density lipoprotein (oxLDL) is not only highly immunogenic but toxic to several cell types. Beta-2-glycoprotein-I (ß2GPI) dampens oxLDL toxicity by forming binary oxLDL/ß2GPI complexes. We evaluated whether circulating oxLDL/ß2GPI complexes are associated to atherosclerosis-related events (ARE) and to venous thromboembolism (VTE). METHODS: In a cross-sectional case-control study, cases were (a) 57 consecutive patients (male/female [M/F] 33/24, mean age 57 [10] years) attending a thrombosis unit for ARE (myocardial infarction [MI] n = 20, peripheral vascular disease n = 7, and ischemic strokes n = 30); (b) 52 consecutive patients (M/F 22/30, mean age 55 [17] years) attending the same unit for unprovoked (VTE); (c) normal controls comprised 90 participants (M/F 35/55, mean age 41 [15] years); and (d) oxLDL/ß2GPI complexes were measured by immunoassay and resulting levels divided into quartiles. RESULTS: The odds ratio (OR) of ARE was greater in the fourth and second quartiles than in the first quartile (8.5 and 6.0, respectively); the OR of developing MI was greatest in the fourth quartile (17.8). By multivariable analysis with age, sex, smoking, lipid status, statin, and ARE phenotypes as independent variables and oxLDL/ß2GPI as the dependent variable, only MI predicted oxLDL/ß2GPI ( P < .0001). CONCLUSIONS: OxLDL/ß2GPI may be regarded as a marker of ARE, in particular of MI.

Atherogenic antiphospholipid antibodies in antiphospholipid syndrome.

Macrophage uptake of oxidized LDL (oxLDL) plays a critical role in early stages of atherosclerosis. We previously reported that oxLDL forms stable complexes with beta2-glycoprotein I (beta2GPI), and that these complexes were frequently present in the sera of patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). oxLDL/beta2GPI complexes were shown to be antigenic targets for autoantibodies present in APS. To understand the role of autoantibodies in accelerated atherosclerosis of SLE and APS, we investigated the binding characteristics of beta2GPI and oxLDL to mouse macrophages, and the effect of anti-beta2GPI and anti-oxLDL autoantibodies on this macrophage binding. IgM anti-oxLDL antibody (derived from Apoe -/- mouse) showed inhibitory effect on oxLDL binding to macrophages. Although beta2GPI partly inhibited oxLDL binding to macrophages, IgG anti-beta2GPI autoantibody (derived from APS model mouse) showed pro-atherogenic property by promoting the binding of oxLDL/beta2GPI to macrophages.

Determination of oxidized low-density lipoproteins (ox-LDL) versus ox-LDL/beta2GPI complexes for the assessment of autoimmune-mediated atherosclerosis.

The immunolocalization of oxidized low-density lipoproteins (ox-LDL), beta2-glycoprotein I (beta(2)GPI), CD4(+)/CD8(+) immunoreactive lymphocytes, and immunoglobulins in atherosclerotic lesions strongly suggested an active participation of the immune system in atherogenesis. Oxidative stress leading to ox-LDL production is thought to play a central role in both the initiation and progression of atherosclerosis. ox-LDL is highly proinflammatory and chemotactic for macrophage/monocyte and immune cells. Enzyme-linked immunosorbent assays (ELISAs) to measure circulating ox-LDL have been developed and are being currently used to assess oxidative stress as risk factor or marker of atherosclerotic disease. ox-LDL interacts with beta(2)GPI and circulating ox-LDL/beta(2)GPI complexes have been demonstrated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It has been postulated that beta(2)GPI binds ox-LDL to neutralize its proinflammatory and proatherosclerotic effects. Because beta(2)GPI is ubiquitous in plasma, its interaction with ox-LDL may mask oxidized epitopes recognized by capture antibodies potentially interfering with immunoassays results. The measurement of ox-LDL/beta(2)GPI complexes may circumvent this interference representing a more physiological and accurate way of measuring ox-LDL.

Antiphospholipid antibodies in patients with coronary artery disease: new cardiac risk factors?

Antiphospholipid antibodies (aPL) have been implicated in the pathogenesis of coronary artery disease (CAD). We evaluated the presence of aPL in patients with chest pain/acute coronary syndromes (ACS) to determine if aPL were associated with the presence and severity of CAD, adverse outcomes, and other coronary risk factors. Patients with chest pain/ACS were evaluated for aPL prior to diagnostic and therapeutic investigations. Coronary angiograms were graded according to the severity of disease. Risk factors, including family histories, were assessed and patients were followed for adverse outcomes. To date, 232 patients (116 M, 116 F, mean age 63 years) with a mean follow-up of 9 months were studied. Thirty-seven percent (86/232) were positive for one or more aPL. More women, 49/86 (57%), were aPL positive versus men, 37/86 (43%). The presence of aPL appeared associated with both presence and severity of CAD (P = 0.176 women; P = 0.163 men). In patients undergoing procedures (angioplasty, stent, bypass), aPL was significantly associated with both an increase in adverse cardiac outcomes (P = 0.045) and extracardiac thrombotic events (P = 0.033). Anti-beta2 glycoprotein-1 (abeta2GP1) was the most frequent aPL, occurring in 68.5% of aPL-positive patients with CAD. Anticardiolipin antibody (aCL) occurred in only 7.4%. IgM isotypes were the most frequent for all categories of aPL (range 55-90%). Family history of antiphospholipid syndrome (APS)-related events was more significant in aPL-positive than aPL-negative individuals (P = 0.027).

Urinary 11-Dehydro-Thromboxane B2 and Mortality in Patients With Stable Coronary Artery Disease.

Antiplatelet therapy with aspirin has been shown to reduce adverse outcomes in patients with coronary artery disease (CAD). Aspirin irreversibly inhibits platelet cyclooxygenase-1 and attenuates thromboxane A2 (TXA2)-mediated platelet aggregation, but there is variable suppression of cyclooxygenase-1. From a cohort of patients with stable CAD, we performed blinded, detailed chart abstraction, and measured urinary 11-dehydro-thromboxane B2 (11dhTxB2), an inactive metabolite of TxA2 from frozen samples. There were 327 men (73%) and 122 women (27%) with a mean age (±SD) of 67 ± 10 and 65 ± 10 years, respectively. A positive linear trend for age was observed among tertiles of 11dhTxB2 (p trend = 0.01). Higher proportions of women (p = 0.001), chronic obstructive pulmonary disease (p trend = 0.0003), and heart failure (p trend = 0.003) were observed in the upper tertile of 11dhTxB2. Sixty-seven patients (14.9%) died over a median follow-up of 1,149 days and 87.5% of the deaths were due to cardiovascular causes. Twenty-six nonsurvivors (38.8%) were treated with P2Y12 receptor antagonists versus 161 survivors (42.2%; p = 0.61). By stepwise Cox proportional hazards analysis, we identified that patients in the middle (hazard ratio 7.14; 95% CI 2.46 to 20.68) and upper tertiles (hazard ratio 9.91; 95% CI 3.45 to 28.50) had higher risks for mortality after adjusting for age and co-morbidities. In conclusion, urinary concentration of 11dhTxB2 was a strong independent risk factor for all-cause mortality among patients with stable CAD on aspirin therapy and may be a marker for patients with CAD who require more intensive secondary prevention measures.

Residual thromboxane activity and oxidative stress: influence on mortality in patients with stable coronary artery disease.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2α (8-IsoPGF2α)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2α in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2α. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2α were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2α below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2αadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2αadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2α, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

Accelerated atheroma in the antiphospholipid syndrome.

Increased cardiovascular morbidity and mortality due to the pre-mature or accelerated development of atherosclerosis has been reported in patients with systemic autoimmune diseases such as systemic lupus erythematosus. These findings motivated a great deal of research into the role of autoimmunity in atherogenesis. The relationship between atherosclerosis and cholesterol metabolism to atherosclerosis has been well established. However, the participation of newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions.

Oxidized Low-Density Lipoprotein-ß2-Glycoprotein I Complex But Not Free Oxidized LDL Is Associated With the Presence and Severity of Coronary Artery Disease.

Oxidized low-density lipoprotein (oxLDL) and ß2-glycoprotein I (ß2GPI) have been identified in human atherosclerotic lesions and when complexed have been implicated as a pro-atherothrombotic antigen. We examined the association of free oxLDL and oxLDL-ß2GPI complex in patients with coronary artery disease who underwent elective cardiac catheterization. Serum was collected from patients with suspected coronary artery disease immediately before elective cardiac catheterization who were either treated (n = 385) or not treated (n = 150) with statins and from healthy volunteers (n = 134). OxLDL and oxLDL-ß2GPI complex levels were determined by enzyme-linked immunosorbent assay. Disease severity was defined angiographically as none-minimal (<20%), moderate (20% to 75%), and severe (>75%) luminal diameter obstruction of any major coronary vessel. Both oxLDL and oxLDL-ß2GPI complex were lower in patients on statins (p <0.001). In statin-naive patients, oxLDL-ß2GPI complex, but not free oxLDL, was associated with severe coronary artery disease (p = 0.036). However, no association was observed in patients on statins. LDL4 and triglycerides increased with oxLDL-ß2GPI complex quartiles (p = 0.001). OxLDL-ß2GPI complex (>0.32 U/ml) was predictive of severe atherosclerosis by receiver-operating characteristic curve analysis in statin-naive patients (area under the curve 0.66, p = 0.002). In conclusion, oxLDL-ß2GPI appears more predictive of coronary artery disease severity than oxLDL alone in statin-naive patients.

Respirometric characterization of aerobic sulfide, thiosulfate and elemental sulfur oxidation by S-oxidizing biomass.

Respirometry was used to reveal the mechanisms involved in aerobic biological sulfide oxidation and to characterize the kinetics and stoichiometry of a microbial culture obtained from a desulfurizing biotrickling filter. Physical-chemical processes such as stripping and chemical oxidation of hydrogen sulfide were characterized since they contributed significantly to the conversions observed in respirometric tests. Mass transfer coefficient for hydrogen sulfide and the kinetic parameters for chemical oxidation of sulfide with oxygen were estimated. The stoichiometry of the process was determined and the different steps in the sulfide oxidation process were identified. The conversion scheme proposed includes intermediate production of elemental sulfur and thiosulfate and the subsequent oxidation of both compounds to sulfate. A kinetic model describing each of the reactions observed during sulfide oxidation was calibrated and validated. The product selectivity was found to be independent of the dissolved oxygen to hydrogen sulfide concentration ratio in the medium at sulfide concentrations ranging from 3 to 30 mg S L(-1). Sulfide was preferentially consumed (SOURmax = 49.2 mg DO g(-1) VSS min(-1)) and oxidized to elemental sulfur at dissolved oxygen concentrations above 0.8 mg DO L(-1). Substrate inhibition of sulfide oxidation was observed (K(i,S(2-))= 42.4 mg S L(-1)). Intracellular sulfur accumulation also affected negatively the sulfide oxidation rate. The maximum fraction of elemental sulfur accumulated inside cells was estimated (25.6% w/w) and a shrinking particle equation was included in the kinetic model to describe elemental sulfur oxidation. The microbial diversity obtained through pyrosequencing analysis revealed that Thiothrix sp. was the main species present in the culture (>95%).

Oxidized low-density lipoprotein/beta2-glycoprotein I complexes and autoantibodies in patients with type 2 diabetes mellitus.

Diabetes mellitus (DM) is associated with a high incidence of atherosclerotic cardiovascular complications that result from chronic metabolic abnormalities such as hyperglycemia-induced oxidative stress. The oxidative-modification of low-density lipoproteins (oxLDL) and oxLDL/beta(2)-GPI complex formation have been reported in patients with autoimmune disorders. OxLDL/beta(2)-GPI complexes and autoantibodies to these complexes were measured by ELISA in serum samples from 50 type 2 DM patients and 50 age/sex-matched healthy controls. Mean OD for oxLDL/beta(2)-GPI complexes in DM was 0.099 +/- 0.065 with 50% of patients reacting above the assay cutoff (P < 0.001 vs. controls). Mean OD for controls was 0.037 +/- 0.015 with 2% positives. Thirty-six (72%) DM patients were taking cholesterol-lowering statins and had a significantly lower mean OD complex level (0.092 +/- 0.071, P = 0.05) compared to patients not taking statins (0.112 +/- 0.05). Mean OD for IgG anti-oxLDL/beta(2)-GPI antibodies in DM was 0.157 +/- 0.112, similar to the controls (0.146 +/- 0.098, P = 0.328). Increased serum levels of oxLDL/beta(2)-GPI complexes may be a consequence of oxidative stress and LDL modification in DM. Lower levels of oxLDL/beta(2)GPI complexes in DM patients taking statins are in agreement with the antioxidant and antithrombotic properties of these drugs. No significant IgG autoantibody production was observed in this group of DM patients. The interaction of oxLDL with beta(2)-GPI in circulation suggests the intriguing possibility that oxLDL/beta(2)-GPI complexes may also play a role in the development of atherosclerosis and/or cardiovascular complications in DM.

Pregnancy loss and endometriosis: pathogenic role of anti-laminin-1 autoantibodies.

Laminin-1 is a major multifunctional glycoprotein that forms an integral part of the scaffolding network of basement membranes, and is the earliest synthesized component during embryogenesis. This protein (alpha1beta1gamma1) plays an important role in basement membrane assembly and epiblast differentiation during embryonic development. Anti-laminin-1 autoantibodies are known to cause infertility and recurrent spontaneous abortion in animals. Recently, we reported that the presence of IgG anti-laminin-1 antibodies (Abs) in the blood is significantly associated with recurrent first-trimester miscarriages and subsequent negative pregnancy outcomes. Interestingly, these antibodies are also strongly associated with infertility, especially infertility caused by endometriosis. Laminin-alpha1, laminin-beta1, and laminin-gamma1 mRNAs were also detected in 90% of endometriotic lesions, and all laminin-alpha1, laminin-beta1, and laminin-gamma1 chains were localized to the basement membranes of glandular epithelium in endometriotic peritoneal lesions. ELISA showed specific reactivity of the autoantibodies to a particular region of the laminin-1 molecule, that is, the alpha1 chain G domain. IgM monoclonal anti-laminin-1 Abs, which we recently established, also recognized the G domain and cross-reacted with human alpha1 chain located in the basement membrane of the glandular epithelium of human endometrium. We also established an animal model that produced high titers of anti-laminin-1 Abs after immunization with mouse laminin-1. Anti-laminin-1 Abs from the immunized mice caused a higher fetal resorption rate with lower embryonic and placental weights. Thus, anti-laminin-1 Abs may be important in the development of autoimmune-mediated reproductive failures, and the assessment of the such antibodies may provide a novel means for noninvasive diagnosis of endometriosis.

OxLDL/beta2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement.

Oxidized low-density lipoprotein (oxLDL) interacts with beta2GPI, forming oxLDL/beta2GPI complexes. Autoimmune vascular inflammation (and oxidative stress) may promote the formation of these complexes. The coexistence of oxLDL/beta2GPI complexes with autoantibodies to these complexes suggests an active pro-atherogenic role in vascular thrombosis and atherosclerosis. Immunoglobulin G (IgG) anti-oxLDL/beta2GPI antibodies have been regarded as pro-atherogenic, whereas IgM antibodies are thought to be anti-atherogenic. For this study, oxLDL/beta2GPI complexes, IgG, and IgM anti-oxLDL/beta2GPI antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Measurements were taken in two patient groups: (1) those with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA); and (2) those with primary and secondary antiphospholipid syndrome (APS). For oxLDL/beta2GPI complexes, SLE and SSc patients had the highest mean optical densities (ODs) (P <.001), followed by RA (P = .139) and healthy controls. IgG anti-oxLDL/beta2GPI antibody distribution followed the same pattern observed with oxLDL/beta2GPI complexes, SLE and SSc (P <.001), RA (P = .08), and controls. IgM antibodies showed a reverse pattern, with the highest mean OD in RA (P <.001), followed by SSc (P = .007) and SLE (P = 143). Both IgG and IgM anti-oxLDL/beta2GPI antibodies were significantly higher in secondary APS patients compared with SLE controls without APS. In addition, the highest mean OD and prevalence of IgG anti-oxLDL/beta2GPI antibodies were observed in APS patients with a history of arterial thrombosis. These results may reflect the widespread vascular involvement seen in SLE and SSc, in contrast to the relatively low vascular involvement in RA. In SLE and SSc, high serum levels and prevalence of circulating oxLDL/beta2GPI complexes and IgG anti-oxLDL/beta2GPI antibodies indicate significant vascular oxidative stress as well as a possible pathogenic role in autoimmune-mediated atherosclerosis.