OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients

It has been demonstrated that atherosclerosis (ATS) is enhanced in autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in SLE patients than in general population, they do not seem to fully explain the enhanced risk. ATS has the characteristics of an autoimmune chronic disease, involving both the innate and the adaptive immunity. Moreover, it satisfies the four criteria defining an autoimmune disease, proposed by Witebsky and Rose. It has been shown that some autoantibodies, including anti-oxLDL, anti-beta(2)GPI, anti-HSP60/65, and more recently anti-oxLDL/beta(2)GPI, play a key role in the pathogenesis of ATS. However the role of these autoantibodies in accelerated ATS in SLE patients is still controversial. In fact, some of them seem to be proatherogenic and other protective; moreover, it has been demonstrated that induced oral tolerance has a protective role against ATS. We have recently observed that the levels of oxLDL/beta(2)GPI antigenic complexes and their antibodies were higher in patients with SLE than in healthy subjects, but we did not find a clear association between oxLDL/beta(2)GPI complexes and IgG or IgM anti-oxLDL/beta(2)GPI autoantibodies and subclinical ATS in SLE patients. Many other studies are required to explain the role of autoantibodies in the pathogenesis of ATS in SLE patients, because the characteristics of SLE seem to mask their effects for atherogenesis.     

Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound beta 2 glycoprotein I.

AIMS--To determine whether beta 2 glycoprotein I (beta 2GPI) dependent anticardiolipin (aCL) antibodies detected in solid phase enzyme linked immunosorbent assays can also have lupus anticoagulant activity. METHODS--Six anticardiolipin antibodies were affinity purified from patients with these antibodies and lupus anticoagulant activity in their plasma. RESULTS--The anticardiolipin antibodies bound only to anionic phospholipids in the presence of beta 2GPI and bound to beta 2GPI in the absence of phospholipids. Four out of six had lupus anticoagulant activity in the dilute Russell viper venom time test. CONCLUSIONS--The results show that some beta 2GPI dependent aCL are lupus anticoagulants. It is unclear why only some should have lupus anticoagulant activity while others do not.     

Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro.

AIMS--To investigate the effect of beta 2-glycoprotein I (beta 2 GPI) on the thrombin/thrombomodulin dependent activation of protein C; and to determine whether beta 2 GPI dependent anticardiolipin antibodies have any effect. METHODS--Protein C was activated by thrombin in the presence of thrombomodulin and phospholipid vesicles in an in vitro system. The effect of adding purified beta 2 GPI to this system was observed. Affinity purified anticardiolipin antibodies and total IgG from patients with anticardiolipin antibodies and the lupus anticoagulant were studied for their effects on protein C activation in the presence and absence of beta 2 GPI. RESULTS--beta 2-Glycoprotein I had no effect on the activity of preformed activated protein C. When the phospholipid vesicles were incubated with beta 2 GPI before the addition of protein C, the activation of protein C was inhibited in a dose dependent manner. With phosphatidylserine:phosphatidylcholine vesicles at a concentration of 1 microM:2 microM, beta 2 GPI began to inhibit the reaction at a concentration of 15 nM, and at 4 microM (the normal plasma concentration) the activation of protein C was reduced to 40%. Anticardiolipin antibodies had no demonstrable effect. CONCLUSIONS--beta 2-Glycoprotein I inhibits protein C activation in an in vitro system. Its physiological role is unknown but it has potential procoagulant as well as anticoagulant properties. An effect of antiphospholipid antibodies on protein C activation, which might explain their association with thrombosis, could not be shown.     

Placental thrombosis in experimental anticardiolipin antibodies-mediated intrauterine fetal death

PROBLEM: Anticardiolipin (aCL) antibodies are associated with stillbirths, recurrent miscarriages and recurrent in vitro fertilization implantation failure in women. Previous animal studies have demonstrated that these antibodies can cause early fetal demise and implantation failure in mice, but most previous studies have not allowed the immunized mice to proceed to the full term of gestation. METHOD OF STUDY: Mice were immunized with either cardiolipin alone or cardiolipin in combination with beta2-glycoprotein I (beta2GPI) and have studied the effects of these antibodies on pregnancies which were allowed to progress to term. RESULTS: Immunization with cardiolipin alone induced significant levels of anticardiolipin antibodies in mice, but immunization with a combination of cardiolipin and beta2GPI produced even higher levels of antibodies. Mice with elevated levels of anticardiolipin antibodies had poor pregnancy outcomes. This study confirms previous results that anticardiolipin antibodies cause early pregnancy losses and also demonstrates that these antibodies cause stillbirth-like late fetal demise. This study further demonstrated that very high levels of anticardiolipin antibodies cause intrauterine death by facilitating the thrombotic episode in placenta. CONCLUSIONS: The present study concludes that the possible mechanism involves in stillbirth of aCL is possibly because of the thrombotic events of placenta.     

Humoral Immune Response to Human Cytomegalovirus in Patients Undergoing Percutaneous Transluminal Coronary Angioplasty

Possible causal relations between prior human cytomegalovirus (HCMV) infection and atherosclerosis and between HCMV reactivation and restenosis after coronary angioplasty have been suggested. We investigated patterns of antibodies directed to HCMV in 112 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and in a group of sex- and age-matched controls (blood donors without evidence of atherosclerosis). Levels of antibodies to HCMV were measured by enzyme-linked immunosorbent assay (ELISA) of serum samples drawn before and 5 weeks after PTCA. To further differentiate the humoral immune response, we specifically tested antibody reactivity towards four single HCMV proteins (IE2, p52, pp150, and pp65) by recombinant ELISAs. We found that 73% of PTCA patients and 69% of sex- and age-matched controls were seropositive for HCMV (odds ratio, 1.2 [not significant]). The corresponding odds ratios for matched pairs ranged in the recombinant ELISAs from 1.2 to 1.4. Patients had more often high titers of anti-HCMV antibodies (11 versus 4%; odds ratio = 3.3 [0.9 to 15.2]; P = 0.052) and high titers of anti-pp150 antibodies (13 versus 4%; odds ratio = 6.0 [1.3 to 38.8]; P = 0.008). Anti-HCMV immunoglobulin M antibodies were not detected in any patient. There was no evidence of acute HCMV reactivation after PTCA, since the titers of antibodies to the investigated recombinant proteins did not increase at 5 weeks after PTCA. Our results show a limited association between prior HCMV infection and coronary artery disease. We infer that positive anti-HCMV titers are not a major risk factor at the time of disease manifestation. However, this study cannot rule out a possible role of HCMV at earlier stages of the atherosclerotic process. Recombinant ELISAs provide a valuable tool for investigating the antiviral immune response.     

Anticardiolipin antibodies are no marker for survived myocardial infarction

Summary Antiphospholipid antibodies — both the lupus anticoagulant and anticardiolipin antibodies — are closely associated with arterial and venous thrombosis. In this prospective trial the IgM- and IgG-anticardiolipin antibodies in serum were determined in acute and chronic coronary artery disease. Seventy-four unselected males (34–87 years, mean 60) were included in the study. All patients underwent coronary angiography; infectious and autoimmune diseases were exclusion criteria. Sixteen patients had coronary artery disease (group A), 34 showed coronary stenoses with prior infarction (B), and 14 had survived an acute myocardial infarction (C), whereas 10 patients revealed no significant coronary narrowing (D; controls). The major risk factors were the same for all groups. Neither the IgM- nor the IgG-anticardiolipin antibody levels showed any significant difference in the four groups. The severity of coronary artery disease did not correlate to these antibodies. Furthermore, no correlation was found between elevated anticardiolipin antibodies and thrombocyte levels. Thus, a higher anticardiolipin level does not appear to be a marker for recurrent cardiovascular events.ACA anticardiolipin antibodies - CAD coronary artery disease - MPL-U/ml IgM phospholipid-units/ml - GPL-U/ml IgG phospholipid-units/ml     

Antibodies to prothrombin, factor V, and beta2-glycoprotein I and vascular access thrombosis

We studied 88 hemodialysis patients for the presence of antibodies to human factor II (hFII), bovine factor V (bFV), and human beta2-glycoprotein 1 (beta2GPI). Forty-one patients had elevated anti-hFII antibodies, 17 had elevated anti-bFV antibodies, and 9 had elevated anti-beta2GPI antibodies. Fifty-two patients had elevated antibodies to one or more protein. Patients with PTFE grafts had elevated antibodies most frequently (21 [75%] vs. 20 fistulas [45%; p = 0.016 compared with PTFE] and 11 tunneled catheters [68.8%]). Twelve of 13 patients (92.3%) with PTFE grafts and thrombosis had elevated antibody levels, compared with 9 of 15 without thrombosis (60%; p = 0.049). The number of thromboses and mean thrombosis rates were significantly higher in PTFE patients with antibodies (1.24 vs. 0.14 thromboses, p < 0.01; 42.67 vs. 6.44 thromboses/100 patient years, p < 0.05). When analyzed individually, thrombotic complications occurred more frequently in patients with PTFE grafts and elevated anti-bFV antibodies (p = 0.016), but did not correlate with anti-hFII or anti-beta2GPI antibodies. Thrombotic complications did not correlate with elevated antibody levels in patients with AV fistulas or cuffed catheters. In conclusion, hemodialysis patients with PTFE grafts frequently have elevated antibodies to FII, FV, and beta2GPI, and the presence of elevated antibody levels to one or more of these proteins is associated with an increased thrombotic risk. Further studies are necessary to determine whether limiting exposure to bovine thrombin preparations will decrease the incidence of these antibodies and PTFE graft thrombosis.     

Atherosclerosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include “traditional” risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to β2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-β1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.     

Anti-oxLDL antibody isotype levels, as potential markers for progressive atherosclerosis in APOE and APOECD40L mice

In humans and animal models of atherosclerosis, antibodies against oxidized LDL have been associated with atherosclerotic lesion development. It has been suggested that IgM anti-oxLDL antibodies are anti-atherogenic, whereas IgG anti-oxLDL antibodies are pro-atherogenic. In this study, we examined the relation between IgM and IgG antibody levels and atherosclerosis severity in APOE(-/-)CD40L(-/-) mice, which are deficient for IgG and develop moderate advanced atherosclerosis, and compared results with mice developing severe (APOE(-/-)) or no atherosclerosis (C57Bl/6). Mice were followed in time for anti-oxLDL antibodies while on high-fat diet or normal chow. Anti-oxLDL antibody levels were determined by ELISA. Results revealed that 24-week-old APOE(-/-)CD40L(-/-) mice had enhanced IgM anti-oxLDL antibody levels when compared with wild-type mice, but similar levels to those of APOE(-/-) mice. As expected, IgG anti-oxLDL antibody levels were almost absent in APOE(-/-)CD40L(-/-) mice. The transition from early to advanced lesions in APOE(-/-) mice was reflected by elevated IgM anti-oxLDL antibody levels. IgM anti-oxLDL levels did not further increase during progression to more advanced lesions. No relation was found between IgG anti-oxLDL levels and atherosclerosis severity. In conclusion, the severity of advanced atherosclerosis in mice is not reflected by IgM and/or IgG anti-oxLDL antibody levels. Furthermore, less advanced atherosclerotic lesion development in APOE(-/-)CD40L(-/-) mice does not seem to be the result of higher levels of protective IgM anti-oxLDL antibodies. Therefore, our study does not support the idea that the previously observed inconsistency in the relation between anti-oxLDL and atherosclerosis severity is due to differences in antibody isotypes.     

A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis

Restenosis is a major problem for patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Inflammatory processes and genetic factors have been suggested to be involved in the pathogenesis of both atherosclerosis and restenosis. The recently discovered family of Toll-like receptors (TLRs) consists of molecules that initiate signaling after host-pathogen interactions. Recently it has been shown that the TLRs are involved in the development and progression of atherosclerosis by interfering with lipid metabolisms and by mediating inflammation. TLR-2 is a key innate immunity receptor for sensing both endogenous inflammatory mediators and ligands of several microbial pathogens postulated to be involved in atherosclerosis. A frequent single nucleotide polymorphism (SNP) for the TLR-2 gene, resulting in a non-functional receptor, has been described. By genotyping two independent groups of patients receiving PTCA, followed by stent implantation in one group, we found a significantly enhanced frequency of the TLR-2 Arg753Gln SNP in patients with restenosis as compared to those without restenosis (PTCA: 7.21 versus 2.45%, P=0.014; PTCA/stent: 6.86 versus 1.53%, P=0.013). In contrast, a common TLR-4 SNP was similarly distributed among the patient groups investigated. We furthermore compared the frequency of both SNPs in the patients with an age-matched group of individuals without atherosclerosis and found a trend towards a lower frequency of the TLR-4 SNP in the atherosclerotic group (PTCA: 5.58; PTCA/stent: 3.85 versus 7.14%). We conclude that in restenosis a functional TLR-2 is protective and potentially involved in a reaction pattern preventing restenosis. Screening for the TLR-2 Arg753Gln SNP may be of importance for stratifying a patients risk and for preventive and therapeutic measures.L. Hamann and A. Gomma contributed equally to this work     

Relation of preexisting anti-beta2GPI antibodies to infarct size in a rat model.

BACKGROUND: Anti-beta2-glycoprotein I (beta2GPI) antibodies (a subpopulation of antiphospholipid (aPL) antibodies) are associated with a procoagulant state in humans and with enhanced atherosclerosis in experimental animal models. Moreover, the presence of high titers of aPL antibodies in relatively young patients is associated with higher incidence of subsequent myocardial infarction. Herein, we evaluated the role of preexisting high levels of aPL antibodies in determining the size of the infarct induced by permanent ligation of the left anterior descending artery (LAD) in a rat model. METHODS AND RESULTS: A total of 11 Wistar rats were immunized and boosted with 10 microg of the phospholipid binding protein -beta2GPI (a method commonly applied for induction of aPL antibodies). Rats in the control group (n=9) were immunized and boosted with a Freund's adjuvant. Upon development of high anti-beta2GPI antibodies levels, myocardial infarction was induced by ligation of the LAD coronary artery. Rats were sacrificed 7 days later, their lymph nodes were collected for evaluation of cellular immunity to beta2GPI and their hearts were removed for assessment of infarct size and for immunohistochemical stains for iNOS and TGF-beta. beta2GPI-immunized rats exhibited high levels of aPL antibodies (mean optical density of 1.3+/-0.3) as compared with the control group (mean optical density of 0.12+/-0.03; P<.0001). Cellular immunity to beta2GPI was also pronounced as evident by an increased thymidine uptake and by increased interferon gamma secretion by the lymph node cells from beta2GPI-immunized rats. Myocardial infarct size has shown a tendency to be increased in rats induced to develop anti-beta2GPI antibodies (mean size 23+/-9%) as compared with controls (17+/-12%; P<.23). iNOS positive cells in the infarct area of beta2GPI-immunized rats were significantly increased in comparison to the control group (P<.01). Similarly, TGF-beta cell expression was significantly increased in the infarct area of the immunized rats in comparison to the control group (22.6+/-5.1 and 7+/-2.1 per 100 mononuclear inflammatory cells, respectively; P=.01). CONCLUSION: The presence of high levels of aPL antibodies is associated with higher expression of iNOS and TGF-beta and may contribute to myocardial damage.     

Coronary atherosclerosis and interventions: Pathological sequences and restenosis

The primary cause of cardiac morbidity and mortality in developed countries is ischemic (coronary) heart disease. The incidence of this disease is virtually all due to atherosclerosis, and ischemic heart disease is also the most prevalent disease in the industrialized world, causing over 40% of all deaths in the United States and Western Europe. In Japan, the incidence of ischemic heart disease due to coronary atherosclerosis is gradually increasing as well. Compared with the classical nomenclature of atherosclerosis; that is, fatty streak, fibrous plaque and complicated lesions, the term Stary's classification has been universally accepted because it reflects the more recently acquired knowledge about the morphological and biochemical details of the processes in coronary atherosclerosis, which have been obtained by new strategies such as angioscopy, intravascular ultrasound and molecular biological methods. The term Stary's classification has been applied for the coronary atherosclerosis of patients with acute coronary syndrome at the National Cardiovascular Center, for the analysis of predisposing atherosclerosis of these patients. The recent findings regarding acute coronary syndrome resulting from a rupture of coronary atherosclerotic plaques indicate that this syndrome is probably the most important mechanism underlying the sudden onset. It has been found that the risk of plaque rupture may depend more on plaque composition than on plaque size. Plaques rich in soft extracellular lipids and macrophages are possibly more vulnerable to plaque rupture. Two of the goals of the present review are to clarify how plaque disruption occurs and to elucidate the relationship between plaque disruption and coronary risk factors in elderly Japanese patients with acute coronary syndrome. Coronary stents have been shown to be efficacious in the treatment of acute and threatened closure complicating percutaneous transluminal coronary angioplasty (PTCA) and have produced encouraging initial results in the prevention of restenosis. In the autopsy study of restenosis after PTCA, it was observed that dense caps of collagen fibers in the adventitia in the vicinity of the disrupted internal elastic laminae were present in all of the remodeling lesions. It is suggested that remodeling, which resulted in adventitial scarring, is one of the major causative factors of restenosis after PTCA. The long-term success of stenting, however, remains limited by the occurrence of late in-stent restenosis, with an incidence of 20-42% depending on the stent design and the patient population studied. Another aim of the present review is to describe the pathological mechanism of restenosis after PTCA and/or stent replacement and, consequently, the vascular remodeling that occurs around adventitial tissue after PTCA and intimal hyperplasia that is chronically irritated by a foreign body granulomatous reaction after stenting. Finally, the results of the investigation of the effect of a tissue factor pathway inhibitor on the prevention of interventional restenosis is described.     

Detection of 'antiphospholipid' antibodies: a single chromogenic assay of thrombin generation sensitively detects lupus anticoagulants, anticardiolipin antibodies, plus antibodies binding beta(2)-glycoprotein I and prothrombin

The diagnosis of the antiphospholipid syndrome (APS) requires both a typical clinical event plus a persistently positive test in an assay for either anticardiolipin (aCL) antibodies or a lupus anticoagulant (LA). Enzyme linked immunosorbent assays (ELISA) specific for autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) or prothrombin are also used, but none of the tests are adequately sensitive or specific. A chromogenic assay was developed that measures the effect of test antibody or plasma samples on in vitro thrombin formation. It is able to detect both LA and beta(2)GPI-dependent aCL antibodies and may have greater specificity for APS than currently available tests. Using this method various monoclonal antibodies (MoAbs) were examined, from mice immunized with beta(2)GPI, mice with a spontaneous animal model of APS, and from three humans with APS. Plasma and affinity purified antibodies from patients with APS and control groups were also examined. Thrombin inhibition was more sensitive to perturbation by MoAbs than a combination of tests for LA (P < 0.05) and at lower antibody concentrations (12.5 microg/ml versus 100 microg/ml). There was a significant correlation between inhibition of thrombin generation and the level of MoAb reactivity to beta(2)GPI (r = 0.90; P < 0.001) but not to CL (r = 0.06; P = 0.76). Plasma and affinity purified antibodies from patients with APS also inhibited thrombin generation, and significantly more so than patients with aPL from causes other than APS. APS patient samples showed thrombin inhibition in the presence of anti-beta(2)GPI or antiprothrombin antibodies. All MoAbs binding beta(2)GPI showed inhibition of thrombin generation, while MoAbs binding domain I of beta(2)GPI had more LA effect.     

Anti-beta 2-glycoprotein I antibodies of IgM class are linked to thrombotic disorders in young women without autoimmune disease

Antiphospholipid autoantibodies particularly antibodies against beta2-glycoprotein I (anti-beta2GPI) are casually associated with thromboses in patients with autoimmune diseases. However, their exact prevalence and role in the pathogenesis of thromboses in the absence of autoimmune disease is still inconclusive. They might be particularly important when other risk factors of thrombosis are absent. We investigated antiphospholipid antibodies in 68 young women (aged <45yr at onset of the event, without autoimmune disease and with an otherwise low risk of thrombosis) in the stable period following myocardial infarction (MI), lacunar cerebral infarction (LACI) or deep vein thrombosis (DVT) and in 37 healthy age-matched controls. Patients had increased IgM anti-beta2GPI compared to controls (36.0, 11.5-49.5 vs. 17.50, 3.50-30.0 arbitrary units (AU), p<0.001), whereas no difference was obtained in other measured antibodies (anticardiolipin and antiphosphatidylserine (aPS) antibodies of IgG and IgM). IgM anti-beta2GPI positively correlated with some markers of increased coagulation potential and negatively with BMI (r=-039, p<0.005) and other parameters of the metabolic syndrome. In conclusion, we found that levels of IgM anti-beta2GPI are increased in young women suffering arterial or venous thromboses in the absence of other known autoimmune diseases and also in the absence of pronounced classical risk factors. We found that IgM anti-beta2GPI positively correlated with some markers of increased coagulation potential and negatively with parameters of the metabolic syndrome. Thus, it appears that elevated levels of IgM anti-beta2GPI are linked to thrombotic disorders in young women (without autoimmune disease) particularly when classical risk factors or the metabolic syndrome are absent.     

Percutaneous transluminal coronary angioplasty of focal coronary lesions after cardiac transplantation

Summary Transplant coronary artery disease is the greatest impediment to long-term survival beyond the first year after cardiac transplantation. Transplant coronary artery disease shows a heterogeneous angiographic appearance, but focal stenoses can occur alone or at least predominate. Based on an angiographic indication 35 critical focal lesions causing narrowing by 75% or more were treated by PTCA during 23 procedures in seven patients 18–84 months after cardiac transplantation. Three patients each underwent only one procedure and four underwent repeated procedures [2, 3, 4 and 11, respectively]. Primary success was achieved without any complication in 35 of 35 lesions (100%). The mean degree of stenosis was reduced from 86±9% to 28±17% (P<0.001). The rate of restenosis was 18/29 (62%) at a mean of 4 months after angioplasty. Four patients are alive and free of adverse effects (symptoms, myocardial infarction, repeated percutaneous transluminal coronary angioplasty, retransplantation) 16±10 months after their last angioplasty. One patient underwent a successful second heart transplantation 26 months after the first angioplasty. Two patients died, 1 and 31 months after the last angioplasty. In conclusion, percutaneous transluminal coronary angioplasty can be performed safely with an excellent primary success rate in critical focal transplant coronary artery disease. The rate of restenosis is higher than in native coronary artery disease. Long-term follow-up depends on the individually variable accelerated nature of graft atherosclerosis.Abbreviations PTCA percutaneous transluminal coronary angioplasty - TxCAD transplant coronary artery disease - HTX heart transplantation - LAD left anterior decending artery - CFX circumflex artery - RCA right coronary artery     

Overcommitment predicts restenosis after coronary angioplasty in cardiac patients

The objective of this study is to examine the role of a particular stress-enhancing psychosocial risk factor, termed overcommitment, in predicting restenosis after successful percutaneous transluminal coronary angioplasty (PTCA). Overcommitment defines a personal pattern of coping with demands characterized by excessive striving in combination with a strong desire of being approved and esteemed. One hundred six consecutive male patients with coronary artery disease who underwent PTCA were followed over a mean of 12 months. The restenosis rate as defined by quantitative angiography was 34%. Multivariate analysis revealed independent effects of high density lipoprotein cholesterol (odds ratio [OR] 3.19), age (OR 3.43), and overcommitment (OR 2.86) on risk of restenosis. In conclusion, a stress-enhancing psychosocial person characteristic termed overcommitment acts as an independent predictor of coronary restenosis after PTCA. As overcommitment is subject to cognitive-behavioral intervention, results have implications for a more comprehensive approach to secondary prevention in cardiac patients. This research was supported by the German Research Foundation (DFG-SFB 242/D18). We thank Dr. Myriam Valk-Draad for her collaboration.     

Oxidation of LDL and its clinical implication

Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis. Oxidized LDL (oxLDL) represents a variety of modification of both lipid and apolipoprotein B (apoB) components by lipid peroxidation. This promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. Recent findings also suggest that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) within atherosclerotic lesions and that these complexes appear in the circulation. Autoantibodies (auto-Abs) against oxLDL/beta(2)GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). These autoantibodies significantly correlate with arterial thrombosis. IgG auto-Abs having similar specificity emerge spontaneously in NZWxBXSB F1 mice, which generally are considered to be an animal model of APS, and these mice produce a monoclonal IgG auto-Ab (WB-CAL-1) against oxLDL/beta(2)GPI complexes. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages, which suggests that such IgG auto-Abs are pro-atherogenic. In contrast, IgM anti-oxLDL natural Abs found in the atherosclerosis-prone mice have been proposed to be protective. The presence of such Abs in humans has been documented in many publications but their exact pathophysiological significance remains unclear. In this article, we review recent progress in our understanding of the clinical significance of oxidation of LDL, formation of oxLDL complexes, and Abs in atherosclerotic and/or autoimmune disease.     

Anti-idiotypes to Oxidized LDL Antibodies in Intravenous Immunoglobulin Preparations--Possible Immunomodulation of Atherosclerosis

Objective : The aim of this study was to examine whether intravenous immunoglobulin (IVIg) preparations contain anti-oxLDL and anti-anti-oxLDL antibodies. Background : Oxidized low-density lipoprotein (oxLDL) is one of the major players in atherogenesis. IVIg can reduce atherosclerosis in experimental animal models. Methods : Six commercial IVIg preparations were tested for the presence of anti-oxLDL antibodies by EIA. Inhibition studies were performed with the different IVIg preparations and IgGs purified from a pool of sera from patients with high anti-oxLDL antibody levels. Absorption assays were carried out to evaluate the presence of anti-idiotypes against anti-oxLDL antibodies in IVIg preparations. Results : IVIg preparations tested had various degrees of reactivity towards oxLDL. Absorption experiments suggested that the reactivity was specific because it could be effectively absorbed by oxLDL and not by an irrelevant antigen PPD. The reactivity was smaller than that observed with the IgG from the pool with high anti-oxLDL antibody levels. Inhibition studies with IVIg demonstrated 20-45% inhibition of anti-oxLDL binding to oxLDL, compared to 76% inhibition by the pool with high anti-oxLDL levels. To investigate the presence of anti-idiotypes against anti-oxLDL antibodies within IVIg, F(ab') 2 fragments of IVIg IgG were used to absorb IgG F(ab') 2 fragments from the pool of sera with high anti-oxLDL levels. The decreased binding to oxLDL of the absorbed supernatants shows that IgG F(ab') 2 fragments of the IVIg preparations had high inhibitory capacities ranging from 65 to 90%. Conclusions : IVIg preparations contain both anti-oxLDL and anti-anti-oxLDL activity. This finding may explain the immunomodulating effect of IVIg in atherosclerosis.     

T lymphocyte activation and restenosis after percutaneous transluminal coronary angioplasty.

We investigated the relation between the activation of T lymphocytes and the occurrence of restenosis after percutaneous transluminal coronary angioplasty (PTCA) in 10 stable angina patients. Recent studies have suggested that PTCA causes an inflammatory response, which may affect restenosis after angioplasty. Soluble interleukin-2 receptor (sIL-2R) is a useful marker to evaluate the activation of T lymphocytes. sIL-2R was measured before and 2 h after successful PTCA, and 3-month follow-up coronary angiography was done to observe restenosis. Four of 10 patients showed restenosis. The restenosis group of 4 patients had a higher level of sIL-2R after PTCA than the no-restenosis group of 6 patients (495 vs. 274 U/ml, p < 0.01). This study suggests that sIL-2R may offer prognostic information after elective PTCA and identify a subgroup of patients at high risk for clinical restenosis in a few months.