Systemic lupus erythematosus: a model for atherogenesis?

S. Manzi

University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA


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Young women with systemic lupus erythematosus (SLE) have strikingly high rates of coronary heart disease [1–4]. Before we can solve the mystery of why these young women are so afflicted, we must first explore our understanding of cardiovascular disease in the general population. Only by coupling our knowledge of the pathogenesis of SLE and atherosclerosis and examining the risk factors common to both diseases can we begin to unravel the complexity of why these disease processes are so frequently linked.


    Epidemiology of cardiovascular disease in women
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A great misperception is that death from cardiovascular disease is not a major health threat for women. On the contrary, cardiovascular disease, particularly coronary heart disease and stroke, is the leading killer of women in America. In recent years, it has accounted for nearly half of all deaths in women, more than all forms of cancer combined [5]. Significant ethnic differences exist in cardiovascular disease mortality, which is 31% higher in Black than in White females [5]. Cardiovascular disease is also one of the leading causes of disability in women [6]. Estimates of disability in women survivors with coronary heart disease and stroke aged 55–64 yr approximate 36% and 62%, respectively [7]. Previous reports suggest that women incur more than half the costs (estimated to be $274 billion in 1998) of cardiovascular disease, including lost productivity from disability [5].

Although coronary heart disease is the leading cause of death among women, coronary events are uncommon before the age of 55 yr [8]. Women lag 10–20 yr behind men in the incidence of myocardial infarction, but this female advantage diminishes with age [8, 9]. Although most of the classic risk factors for coronary heart disease in men are also found in women, the magnitude of their effects may be different [9, 10]. The most dramatic example is diabetes mellitus, which is a stronger risk factor for coronary heart disease in women than in men and is the most common cause of premature coronary heart disease in women [11]. Other conditions that lessen the female advantage include familial hypercholesterolaemia [12] and premature menopause [13].

Less publicized entities associated with premature coronary heart disease are rheumatoid arthritis [14–16] and SLE [1–4]. It has been well proven that women with SLE are at significant risk of premature cardiovascular disease, now one of the leading causes of death in this population.


    Potential risk factors for cardiovascular disease in SLE
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Classical risk factors for cardiovascular disease in SLE appear to be similar to those in the general population: hypercholesterolaemia, diabetes mellitus, smoking, obesity, hypertension, and sedentary lifestyle [1, 2, 17]. In a recently reported study, the incidence of myocardial infarction and stroke in SLE were significantly increased, even after controlling for expected events based on known population-based risk models, suggesting that the diagnosis of SLE or its treatment is the strongest known risk factor for cardiovascular disease [18].

Treatment with corticosteroids has been implicated as a risk factor for atherosclerosis [2, 19, 20]. Whether corticosteroids are directly atherogenic or whether they are causally related to atherosclerosis through enhancement of cardiovascular disease risk factors such as hyperlipidaemia, hyperglycaemia, hypertension, or obesity remains unclear [21]. In addition, corticosteroids may be a proxy for severe disease, since patients with severe lupus are more likely to be treated with higher doses of corticosteroids for longer periods of time.

Renal disease, seen in up to 50% of SLE patients, may be a risk factor for atherosclerosis. Endothelial cell damage produced by immune complexes, or other mediators of inflammation, may be responsible for activation of the coagulation system in patients with lupus nephritis, resulting in elevated plasma and urine levels of fibrinogen, a precursor of fibrin. Plasma fibrinogen levels have been reported to be higher in non-lupus post-menopausal women than in both pre-menopausal women and women taking oestrogen therapy [22]. Elevated fibrinogen levels have been linked to the risk of future heart disease in women [23]. Increased fibrinogen, along with the abnormal lipid profiles and hypertension frequently seen in patients with nephritis, may result in an increased risk of cardiovascular disease in lupus.


    Parallels between the pathogenesis of SLE and atherosclerosis
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Chronic inflammation
It is currently believed that atherosclerosis in the general population results from a combination of numerous risk factors. In addition to traditional risk factors, inflammatory processes are now suspected to be important in atherogenesis [24]. In particular, the inflammatory processes associated with vascular injury are thought to mediate the development of atherosclerotic lesions. Epidemiological observations have linked inflammation with cardiovascular events. C-reactive protein, an acute phase reactant, was shown to predict independently the risk of future myocardial infarction and stroke in men with otherwise favourable risk factor profiles [25], people with multiple risk factors [26], and people with unstable angina [27].

Inflammatory processes probably contribute to atherogenesis in SLE, a disease characterized by chronic inflammation. This author's hypothesis is that the pathogenesis of cardiovascular disease in lupus is multifactorial, due to an interaction between traditional cardiovascular risk factors and inflammation-induced and antiphospholipid antibody-mediated vascular injury/ thrombosis from the underlying disease. Corticosteroid treatment and renal disease with resulting hypertension may accelerate the atherosclerotic process in lupus. Furthermore, the immune dysregulation characteristic of SLE probably plays an important role in atherogenesis.

Endothelial cell injury
In the ‘response to injury’ hypothesis of atherosclerosis, several different sources of injury to the endothelium can lead to endothelial cell dysfunction [28], including immune complexes, viruses, and other toxins such as homocysteine, all of which are also relevant to SLE (Fig. 1Go). Such injury results in increased permeability and adhesiveness of the endothelium, procoagulative properties, and vasoactive molecule expression [24]. A prolonged inflammatory response with inadequate down-regulation is characteristic of SLE and may actually be an important facilitator of atherogenesis in these patients.



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FIG. 1. Injury to the vascular endothelium is one of the earliest changes that occurs in atherogenesis. Sources of such injury can be mechanical in nature or arise from immune-mediated processes, viral infection, or toxins such as homocysteine. The resultant endothelial dysfunction leads to altered permeability of the endothelium, increased affinity for leucocytes and platelets, production of vasoactive molecules, and induction of procoagulant properties. In SLE, C1q-fixing immune complexes may be a source of injury to the endothelium, resulting in expression of cell adhesion molecules (ICAM-1, VCAM-1). Interactions between CD40 on endothelial cells and CD40L can stimulate expression of ICAM-1, VCAM-1, and E-selectin. LDL particles are also a major source of injury to the endothelium. When LDL particles are trapped in the arterial wall they become progressively oxidized and can be internalized by macropohages, resulting in the formation of foam cells. Antibodies to oxLDL may actually facilitate foam cell formation. The inflammatory response also stimulates the migration and proliferation of smooth muscle cells that together with T cells and foam cells form the fatty streak. Continued cell influx and smooth muscle proliferation leads to formation of the fibrous plaque. As the fibrous plaque grows, it may protrude into the arterial lumen and impede blood flow, or may rupture or fissure resulting in occlusive thrombosis, ultimately leading to the ischaemic event. (Adapted from [28].)

 
Entrapment and subsequent oxidation of low density lipoprotein (LDL) at the site of endothelial injury is an important step in the formation of an atherosclerotic plaque. Endothelial cell adhesion molecules, whose expression is up-regulated, bind and recruit monocytes/macrophages and T lymphocytes to the site of injury. The inflammatory cells then migrate and localize subendothelially. The macrophages ingest oxidized LDL (oxLDL) and, in conjunction with T cells and smooth muscle cells, form the ‘fatty streak’, which can then progress to a fibrous plaque. Rupture of the plaque and formation of a thrombus result in a clinical ischaemic event.

Immune complexes.
In SLE, immune complexes that fix C1q may be a source of arterial injury initiating atherogenesis. These complexes bind to C1q receptors on the endothelium, triggering an up-regulation of adhesion molecules such as E-selectin and intercellular and vascular cell adhesion molecules 1 (ICAM-1 and VCAM-1) on the endothelial surface [29]. These C1q fixing immune complexes have also been shown to down-regulate sterol 27-hydroxylase, leading to increased accumulation of cholesterol in the endothelium [30]. Increased amounts of immunoglobulins, complement components, and C5b-9 complexes have been reported in atherosclerotic lesions [31–33]. One hypothesis of atherogenesis is that this intense immune/inflammatory reaction in the plaque may precipitate plaque ulceration, rupture and thrombosis [34], a process that may be accentuated in SLE.

CD40–CD40L interactions.
CD40 is a molecule expressed on a variety of cells including B lymphocytes, macrophages, fibroblasts, and endothelial cells. Activated T cells transiently express CD40 ligand (CD40L). In SLE, the interaction between CD40L on T cells and CD40 on B cells is involved in the production of pathogenic autoantibodies [35, 36]. Under normal circumstances the immune system allows only transient expression of CD40L. However, patients with SLE express abnormally high levels of CD40L on both T and B cells and the overall number of CD40L-positive cells is increased [35]. Furthermore, in lupus nephritis patients, CD40 expression is up-regulated on endothelial cells.

The binding of CD40L to CD40 on endothelial cells results in increased expression of VCAM-1, ICAM-1, and E-selectin [37], adhesion molecules important in facilitating vascular inflammation both in SLE and in atherosclerosis. Furthermore, CD40L induces the release of interleukin-1 by vascular cells, potentially enhancing the inflammatory response [38]. In genetically modified mice with hypercholesterolaemia that are deficient in apolipoprotein E, ICAM-1 is increased at lesion-prone sites [39]. Inhibition of CD40 with blocking antibodies reduced lesion formation in these mice [40]. Thus, increased CD40–CD40L interactions may have implications in both the pathogenesis of SLE and the premature atherosclerosis seen in this population.

Autoantibodies.
Antiphospholipid antibodies provide additional evidence for immune-mediated atherogenesis. The most common association of antiphospholipid antibodies in SLE is with venous and arterial thromboembolic events, stroke, and recurrent fetal loss [41]. Elevated levels of antibodies to cardiolipin, a phospholipid, have been associated with myocardial infarction in non-lupus patients [42, 43] and with macroangiopathy in diabetics [44]. Antibodies to cardiolipin may recognize several different antigenic structures; some antibodies bind the lipid component and others bind ß2-glycoprotein I or prothrombin [45, 46]. Interestingly, there is evidence that some anticardiolipin antibodies may be directed against cross-reactive epitopes common with oxLDL. The presence of antibodies binding to oxLDL is considered a marker of atherosclerosis [47] and has been reported to be predictive of future myocardial infarction [43, 48].

Several investigators have demonstrated that antibodies to oxLDL were higher in SLE patients than control subjects and correlated with anticardiolipin antibody levels [49, 50]. The recognition of oxLDL by anticardiolipin antibodies may be partially explained by several observations. Anticardiolipin antibodies of the anti- ß2-glycoprotein I type may recognize oxLDL in complex with ß2-glycoprotein I [51]. Binding of antibodies to ß2-glycoprotein I–oxLDL complexes may increase LDL uptake into macrophages via Fc receptors, promoting the formation of the fatty streak (Fig. 1Go). Furthermore, some antiphospholipid antibodies have been shown to be directed against oxidized phospholipids [52].

The significance of these related observations is not completely understood, but one could speculate that these oxidative processes result in the generation of a common antigenic epitope recognized by both antibodies to phospholipid and oxLDL. In support of this theory is the observation that lysophosphatidylcholine (LPC) is a major factor in the antigenicity of oxLDL [53] and has been found in atherosclerotic plaques [54]. It was recently reported that patients with SLE had elevated levels of antibodies to both oxLDL and LPC [55]. LPC can also be generated enzymatically by phospholipase A2 hydrolysis of phosphatidylcholine, a major phospholipid component of cellular membranes. This is of particular relevance in SLE where elevated levels of phospholipase A2 expression and activity have been documented [56]. In this case both oxidation of LDL and hydrolysis of phospholipid result in a common product of known antigenicity.

Apolipoprotein A1 (apo A1), the major protein component of high-density lipoprotein (HDL) that acts as an acceptor of cholesterol from peripheral blood monocytes, is important in the prevention of atherosclerosis [57]. A high prevalence of antibodies to apo A1 has also been documented in the sera of patients with SLE [58]. It is possible that antibodies to apo A1 may impede the uptake of cholesterol into HDL, although this remains to be determined.

Infectious agents.
A role for infectious agents has been proposed in the pathogenesis of atherosclerosis [59, 60]. In the ‘response to injury’ model, infectious agents may serve as a cause of vascular injury or may potentiate injury by stimulating an inflammatory response. Two organisms currently considered likely candidates in atherogenesis are Chlamydia pneumoniae and cytomegalovirus (CMV). Many studies have documented a serological association between C. pneumoniae infection and the development of atherosclerosis [61, 62]. High CMV antibody levels were reported in patients requiring cardiovascular surgery [63], and in the Atherosclerosis Risk in Communities (ARIC) study CMV seropositivity was reported to be correlated with asymptomatic carotid artery wall thickening [64]. Furthermore, pathological and microbiological evidence has confirmed the presence and viability of C. pneumoniae and CMV in atherosclerotic plaques [65]. In vitro studies demonstrated that infection of endothelial cells with CMV resulted in divergent patterns of E-selectin, ICAM-1, and VCAM-1 expression [66] and promoted endothelial procoagulant properties [67].

Although the evidence is circumstantial, infectious agents have gained increasing attention as potential contributors to the development of SLE. They may initiate or flare SLE by disturbing immunoregulation, causing tissue damage leading to the release of autoantigens, or by eliciting a specific immune response by molecular mimicry. Of particular interest are the Epstein–Barr virus [68, 69] and herpes zoster [70]. Although viral infection has not been examined in association with atherosclerosis in lupus, it is interesting to speculate that viral factors may play a role in the premature atherosclerosis seen in this population.

Other sources of endothelial injury.
Another source of potential vascular injury in lupus is elevated homocysteine levels. Homocysteine may have both direct and indirect injurious effects on the endothelium [71, 72]. It is prothrombotic, increases collagen production, and decreases the availability of nitric oxide [73–75]. Both the Physicians' Health Study and the Framingham Heart Study reported an association between homocysteine and an increased relative risk of coronary artery disease, stroke, and carotid vascular disease [76, 77]. Homocysteine was elevated in one population of lupus patients and was associated with arterial thrombosis [78]. The reasons for hyperhomocysteinaemia in SLE are unclear, and may include dietary- and/or treatment-related factors.


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We must redirect our focus on the aetiology of cardiovascular disease in SLE to include non-traditional risk factors such as immune and inflammatory mediators. From an epidemiological standpoint, the relationship between these immunological and inflammatory markers and disease can be examined, but more sensitive methods of defining cardiovascular disease will be required. Relying on clinical events alone often results in an underestimation of the true prevalence of vascular disease since atherosclerosis may be present for many years before a clinical event occurs. Furthermore, epidemiological studies relying on clinical events as outcomes are difficult since the absolute number of cardiovascular events in SLE is very low. With the advent of sensitive non-invasive screening techniques, such as B-mode ultrasound and electron beam computed tomography (CT), we are now better equipped to measure subclinical vascular disease and associated risk factors.

From a basic science perspective, we should concentrate on the common pathways in the pathogenesis of SLE and atherosclerosis. This effort will involve clarifying the role of CD40–CD40L interactions and antibodies directed against phospholipids and cholesterol-carrying lipoproteins such as LDL and HDL, as well as pursuing common infectious triggers.

When considering strategies for prevention of premature cardiovascular disease in SLE, modifying traditional risk factors will be only a part of the future programmes. It seems likely that the strongest predictors of cardiovascular disease in this population will be immune and inflammatory in nature. I propose that better biological therapies for SLE such as anti-CD40 ligand antibodies will have a greater impact on prevention of atherosclerosis than altering traditional risk factors alone. This concept is supported by findings in post-cardiac transplant vasculopathy. Accelerated coronary atherosclerosis is the leading cause of mortality in cardiac transplant recipients who survive beyond the first year of transplantation [79, 80]. Although the exact pathogenesis of cardiac allograft vasculopathy is not completely understood, considerable evidence suggests that it is an immune-mediated disease that is different from the cell-mediated rejection commonly seen post-transplant [79, 80]. The proliferative disease is limited to the allograft arterial and venous tree, the nature of the allograft vascular involvement is often diffuse, and development of the disease occurs in allografts of animal models with some histocompatibility mismatch but not in isografts. Furthermore, there is evidence to suggest that more aggressive immunosuppressive treatment directed at blocking cellular processes common to the immune response and vascular lesion formation may be effective in reducing or preventing cardiac allograft vasculopathy [81]. One could hypothesize that treatment directed towards specific immune dysregulation in SLE that does not have the unfavourable side-effect profile of agents such as corticosteroids will be beneficial in preventing premature atherosclerosis in this population.

In response to Elizabeth Barrett Conner's eloquent discussion in her 1995 Ancel Keys Lecture on ‘why women are so superior with regard to coronary heart disease?’ [82], one should be quick to acknowledge that like women with diabetes mellitus, women with SLE nearly erase the female advantage. Given the inflammatory and autoimmune nature of SLE and the associated premature development of atherosclerosis, this unique population may provide an interesting model to examine further the process of atherogenesis.


    Acknowledgments
 
This study was supported by the Arthritis Foundation; a grant-in-aid from the American Heart Association; the Lupus Foundation of America, Western Pennsylvania Chapter; NIH/MAC grant 1-P60-AR- 44811 01; NIH/5R01 HL5490002; and NIH/NCRR/GCRC grant 5M01-RR-00056. The author would like to thank Janice Sabatine, PhD, for editorial assistance and manuscript preparation.


    Notes
 
Correspondence to: S. Manzi, Room 5722, Biomedical Science Tower, South Wing, 200 Lothrop Street, Pittsburgh, PA 15261, USA. Back


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  1. Manzi S, Meilahn EN, Rairie JE et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol1997;145:408–15.[Abstract]
  2. Petri M, Perez-Gutthann S, Spence D, Hochberg MC. Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med1992;93:513–9.[ISI][Medline]
  3. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med1976; 60:221–5.[ISI][Medline]
  4. Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum1999;42:338–46.[ISI][Medline]
  5. National Institutes of Health, National Heart, Lung, and Blood Institute. Morbidity and Mortality: 1998 chartbook on cardiovascular lung and blood diseases, US Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, Maryland, 1998.
  6. Soldo BJ, Manton KG. Health status and service needs of the oldest old: current patterns and future trends. Milbank Mem Fund Q Health Soc1985;63:286–319.[ISI][Medline]
  7. Eaker ED, Chesebro JH, Sacks FM, Wenger NK, Whisnant JP, Winston M. Cardiovascular disease in women. Circulation1993;88:1999–2009.[ISI][Medline]
  8. Kannel WB, Wilson PW. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med1995;155:57–61.[Abstract]
  9. Mosca L, Manson JE, Sutherland SE, Langer RD, Manolio T, Barrett-Connor E. Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association Writing Group. Circulation1997;96:2468–82.[Free Full Text]
  10. Rich-Edwards JW, Manson JE, Hennekens CH, Buring JE. The primary prevention of coronary heart disease in women. N Engl J Med1995;332:1758–66.[Free Full Text]
  11. Sowers JR. Diabetes mellitus and cardiovascular disease in women. Arch Intern Med1998;158:617–21.[Abstract/Free Full Text]
  12. Feussner G, Wagner A, Ziegler R. Relation of cardiovascular risk factors to atherosclerosis in type III hyperlipoproteinemia. Hum Genet1993;92:122–6.[ISI][Medline]
  13. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. J Am Med Assoc1991;265:1861–7.[Abstract]
  14. Wallberg Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol1997;24:445–51.[ISI][Medline]
  15. Gabriel S, Crowson C, O'Fallon WM. Heart disease in rheumatoid arthritis (RA). [Abstract] Arthritis Rheum1998;9(Suppl.):S132.
  16. Wolfe F, Mitchell DM, Sibley JT et al. The mortality of rheumatoid arthritis. Arthritis Rheum1994;37:481–94.[ISI][Medline]
  17. Manzi S, Selzer F, Sutton-Tyrrell K et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum1999;42:51–60.[ISI][Medline]
  18. Esdaile JM, Abrahamowicz M, Grodzicky T et al. Myocardial infarction and stroke in SLE: markedly increased incidence after controlling for risk factors. [Abstract] Arthritis Rheum1998;41(Suppl. 9):A639.
  19. Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med1975;58:243–64.[ISI][Medline]
  20. Hochberg MC, Petri M. The association of corticosteroid (CS) therapy with coronary heart disease (CHD) in patients with systemic lupus erythematosus (SLE): A meta-analysis. Arthritis Rheum1991;34:R24.
  21. Ettinger WH, Goldberg AP, Applebaum-Bowden D, Hazzard WR. Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids. Am J Med1987; 83:503–8.[ISI][Medline]
  22. Meilahn EN, Kuller LH, Matthews KA, Kiss JE. Hemostatic factors according to menopausal staus and use of hormone replacement therapy. Ann Epidemiol1992;2:445–55.[Medline]
  23. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. J Am Med Assoc1987;258:1183–6.[Abstract]
  24. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med1999;340:115–26.[Free Full Text]
  25. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med1997;336:973–9.[Abstract/Free Full Text]
  26. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol1996;144:537–47.[Abstract]
  27. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med1995;332:635–41.[Abstract/Free Full Text]
  28. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature1993;362:801–9.[ISI][Medline]
  29. Lozada C, Levin RI, Huie M et al. Identification of C1q as the heat-labile serum cofactor required for immune complexes to stimulate endothelial expression of the adhesion molecules E-selectin and intercellular and vascular cell adhesion molecules 1. Proc Natl Acad Sci USA1995;92:8378–82.[Abstract]
  30. Reiss AB, Malhotra S, Javitt NB et al. Occupancy of C1q receptors on endothelial cells by immune complexes downregulates mRNA for sterol 27-hydroxylase, the major mediator of extra-hepatic cholesterol metabolism [Abstact]. Arthritis Rheum1998;41(Suppl. 9):A281.
  31. Bittner V. Atherosclerosis and the immune system. Arch Intern Med1998;158:1395–6.[Free Full Text]
  32. Vlaicu R, Rus HG, Niculescu F, Cristea A. Immunoglobulins and complement components in human aortic atherosclerotic intima. Atherosclerosis1985;55:35–50.[ISI][Medline]
  33. Niculescu F, Hugo F, Rus HG, Vlaicu R, Bhakdi S. Quantitative evaluation of the terminal C5b-9 complement complex by ELISA in human atherosclerotic arteries. Clin Exp Immunol1987;69:477–83.[ISI][Medline]
  34. Niculescu F, Rus H. Atherosclerosis and the immune system. Arch Intern Med1999;159:315.[Free Full Text]
  35. Desai Mehta A, Lu L, Ramsey Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest1996;97:2063–73.[Abstract/Free Full Text]
  36. Koshy M, Berger D, Crow MK. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest1996;98:826–37.[Abstract/Free Full Text]
  37. Hollenbaugh D, Mischel Petty N, Edwards CP et al. Expression of functional CD40 by vascular endothelial cells. J Exp Med1995;182:33–40.[Abstract]
  38. Schonbeck U, Mach F, Bonnefoy JY, Loppnow H, Flad HD, Libby P. Ligation of CD40 activates interleukin 1 beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1 beta. J Biol Chem1997;272:19569–74.[Abstract/Free Full Text]
  39. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol1998; 18:842–51.[Abstract/Free Full Text]
  40. Mach F, Shonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature1998;394:200–3.[ISI][Medline]
  41. Gharavi AE, Wilson WA. The syndrome of thrombosis, thrombocytopenia, and recurrent spontaneous abortions associated with antiphospholipid antibodies: Hughes syndrome. Lupus1996;5:343–4.[ISI][Medline]
  42. Vaarala O, Mänttäri M, Manninen V et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation1995;91:23–7.[Abstract/Free Full Text]
  43. Wu R, Nityanand S, Berglund L, Lithell H, Holm G, Lefvert AK. Antibodies against cardiolipin and oxidatively modified LDL in 50-year-old men predict myocardial infarction. Arterioscler Thromb Vasc Biol1997;17:3159–63.[Abstract/Free Full Text]
  44. Galtier-Dereure F, Biron C, Vies M, Bourgeois V, Schved JF, Bringer J. Vascular complications of diabetes mellitus: what role for phospholipid-binding antibodies? Lupus1998;7:469–74.[ISI][Medline]
  45. Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies. Blood1994; 84:2854–67.[Free Full Text]
  46. Vaarala O, Puurunen M, Lukka M et al. Affinity-purified cardiolipin-binding antibodies show heterogeneity in their binding to oxidized low-density lipoprotein. Clin Exp Immunol1996;104:269–74.[ISI][Medline]
  47. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet1994;344:793–5.[ISI][Medline]
  48. Puurunen M, Manttari M, Manninen V et al. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch Intern Med1994;154:2605–9.[Abstract]
  49. George J, Harats D, Gilburd B, Levy Y, Langevitz P, Shoenfeld Y. Atherosclerosis-related markers in systemic lupus erythematosus patients: The role of humoral immunity in enhanced atherogenesis. Lupus1999;8:220–6.[ISI][Medline]
  50. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo Repo M, Aho K, Palosuo T. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet1993;341:923–5.[ISI][Medline]
  51. Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. Involvement of beta 2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol1997;107:569–73.[ISI][Medline]
  52. Horkko S, Miller E, Dudl E et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest1996;98:815–25.[Abstract/Free Full Text]
  53. Wu R, Huang YH, Elinder LS, Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL. Arterioscler Thromb Vasc Biol1998;18:626–30.[Abstract/Free Full Text]
  54. Elinder LS, Dumitrescu A, Larsson P, Hedin U, Frostegard J, Claesson HE. Expression of phospholipase A2 isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol1997;17:2257–63.[Abstract/Free Full Text]
  55. Wu R, Svenungsson E, Gunnarsson I et al. Antibodies against lysophosphatidylcholine and oxidized LDL in patients with SLE. Lupus1999;8:142–50.[ISI][Medline]
  56. Pruzanski W, Goulding NJ, Flower RJ et al. Circulating group II phospholipase A2 activity and antilipocortin antibodies in systemic lupus erythematosus. Correlative study with disease activity. J Rheumatol1994;21:252–7.[ISI][Medline]
  57. Forte TM, McCall MR. The role of apolipoprotein Al-containing lipoproteins in atherosclerosis. Curr Opin Lipidol1994;5:354–64.[Medline]
  58. Dinu AR, Merrill JT, Shen C, Antonov IV, Myones BL, Lahita RG. Frequency of antibodies to the cholesterol transport protein apolipoprotein Al in patients with SLE. Lupus1998;7:355–60.[ISI][Medline]
  59. Muhlestein JB. Bacterial infections and atherosclerosis. J Invest Med1998;46:396–402.[ISI][Medline]
  60. Vercellotti G. Viruses and atherosclerosis: do they play a pathogenic role? J Invest Med1998;46:403–7.[ISI][Medline]
  61. Thom DH, Grayston JT, Siscovick DS, Wang SP, Weiss NS, Daling JR. Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease. J Am Med Assoc1992;268:68–72.[Abstract]
  62. Melnick SL, Shahar E, Folsom AR et al. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Am J Med1993;95:499–504.[ISI][Medline]
  63. Adam E, Melnick JL, Probtsfield JL et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet1987;2:291–3.[Medline]
  64. Sorlie PD, Adam E, Melnick SL et al. Cytomegalovirus/herpesvirus and carotid atherosclerosis: the ARIC Study. J Med Virol1994;42:33–7.[ISI][Medline]
  65. Chiu B, Viira E, Tucker W, Fong IW. Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery. Circulation1997;96:2144–8.[Abstract/Free Full Text]
  66. Sedmak DD, Knight DA, Vook NC, Waldman JW. Divergent patterns of ELAM-1, ICAM-1, and VCAM-1 expression on cytomegalovirus-infected endothelial cells. Transplantation1994;58:1379–85.[ISI][Medline]
  67. van Dam Mieras MC, Muller AD, van Hinsbergh VW, Mullers WJ, Bomans PH, Bruggerman CA. The procoagulant response of cytomegalovirus infected endothelial cells. Thromb Haemost1992;68:364–70.[ISI][Medline]
  68. James JA, Kaufman KM, Farris AD, Taylor Albert E, Lehman TJ, Harley JB. An increased prevalence of Epstein–Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest1997;100:3019–26.[Abstract/Free Full Text]
  69. Incaprera M, Rindi L, Bazzichi A, Garzelli C. Potential role of the Epstein–Barr virus in systemic lupus erythematosus autoimmunity. Clin Exp Rheumatol1998;16:289–94.[ISI][Medline]
  70. Strom BL, Reidenberg MM, West S, Snyder ES, Freundlich B, Stolley PD. Shingles, allergies, family medical history, oral contraceptives, and other potential risk factors for systemic lupus erythematosus. Am J Epidemiol1994;140:632–42.[Abstract]
  71. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest1986;77:1909–16.[ISI][Medline]
  72. Tsai JC, Perrella MA, Yoshizumi M et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA1994; 91:6369–73.[Abstract]
  73. Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest1993;91:2873–9.[ISI][Medline]
  74. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol1997;17:2074–81.[Abstract/Free Full Text]
  75. Upchurch GR Jr, Welch GN, Fabian AJ et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem1997;272:17012–7.[Abstract/Free Full Text]
  76. Stampfer MJ, Malinow MR, Willett WC et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J Am Med Assoc1992; 268:877–81.[Abstract]
  77. Selhub J, Jacques PF, Bostom AG et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med1995;332:286–91.[Abstract/Free Full Text]
  78. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet1996;348:1120–4.[ISI][Medline]
  79. Rose EA, Smith CR, Petrossian GA, Barr ML, Reemtsma K. Humoral immune responses after cardiac transplantation: correlation with fatal rejection and graft atherosclerosis. Surgery1989;106:203–7; discussion 207-8.[ISI][Medline]
  80. Weis M, von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation1997;96:2069–77.[Abstract/Free Full Text]
  81. Mehra MR, Ventura HO, Chambers R, Smart FW, Stapleton DD. The prognostic impact of immunosuppression and cellular rejection on cardiac allograft vasculopathy: time for a reappraisal. [Abstract] Circulation1995;92(Suppl. I):I245.
  82. Barrett Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation1997;95:252–64.[Free Full Text]
Submitted 9 June 1999; revised version accepted 8 November 1999.