The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus

Patients with systemic lupus erythematosus have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease. Recent advances in the etiology of vascular damage in this disease stress the interplay of lupus-specific inflammatory factors with traditional cardiac risk factors, leading to increased endothelial damage. This review analyzes the putative role that immune dysregulation and lupus-specific factors may play in the pathogenesis of premature vascular damage in this disease. The potential role of various cytokines, in particular type I interferons, in the development of accelerated atherosclerosis is examined. Potential therapeutic targets are discussed.

Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including internal organ damage, which can result in severe morbidity and even death and often requires aggressive immunosuppressive treatment. More than 30 years ago, a bimodal peak in mortality was described in lupus patients, with late increases in death commonly seen as secondary to premature cardiovascular disease (CVD) [1]. Indeed, this enhanced atherosclerotic risk increases with each year of disease duration. Th is is especially the case in young females with SLE, where the CVD risk can be up to 50-fold higher than in age-matched controls [2,3]. While traditional Framingham risk factors likely contri bute to CVD in SLE, they cannot fully account for the increased risk. Instead, the pathogenesis of premature CVD in SLE may rely on factors unique to the disease itself [4].
While systemic infl ammation has been linked to atherosclerosis development in the general population and in specifi c conditions, SLE typically has a lower 'classical infl ammatory burden' compared to what would be seen in rheumatoid arthritis or spondylo arthropathies; yet, lupus is associated with a higher CVD risk than these other diseases. Th is observation suggests that factors that trigger accelerated atherosclerosis in lupus diff er from the typical proinfl ammatory factors (that is, high C-reactive protein (CRP)) linked to 'idiopathic' athero sclerosis. Atherosclerosis progression in lupus patients develops or progresses in 10% of SLE patients per year. Among other factors, this progression is associated with older age at diagnosis and with longer disease duration, supporting the hypothesis that chronic exposure to lupus immune dysregulation promotes CVD [5].

Subclinical and clinical vascular damage in SLE
Premature damage in SLE occurs in both the macro-and microvasculature. Vascular functional abnormalities in lupus are present even shortly after disease diagnosis [6]. SLE patients have signifi cantly decreased fl ow-mediated dilation of the brachial artery and this correlates with increased carotid intima media thickness (IMT) [7]. Additionally, carotid plaque can be detected in 21% of SLE patients under the age of 35 years and in up to 100% of those over the age of 65 years [8]. Aortic atherosclerosis is also increased in SLE [9]. Th ese macrovascular fi ndings correlate with disease activity and disease duration [7][8][9]. Damage to the coronary circulation is also common in SLE patients, with 54% displaying non-calcifi ed coronary plaque [10]. Th ere is also impairment of coronary microvasculature fl ow reserve, even in patients with grossly normal coronary arteries. Th is dysfunction correlates with disease duration and severity, suggesting that microvascular damage and dysfunction are also part of SLErelated CV pathology [11]. Additionally, SLE patients have a higher probability of developing left ventricular hyper trophy, independent of baseline hypertension, again empha siz ing the role of lupus-related factors in CVD damage [12].

Mechanisms of atherosclerosis development in the general population
Various groups have proposed that CVD, endothelial dysfunction and atherosclerosis arise from chronic injury to the endothelium, which allows for invasion of infl ammatory cells and lipid deposition. Current dogma upholds that chronic infl ammation instigates and perpetu ates the atherogenic cycle. Factors such as oxidized low density lipoprotein (LDL) activate the endothelium to secrete chemokines, which recruit infl ammatory cells, including T lymphocytes, dendritic cells (DCs) and monocytes. Th ese monocytes diff erentiate into macro phages and foam cells under the infl uence of locally secreted factors [13]. Various stimuli, including cholesterol crystals, then activate macrophages and foam cells to secrete infl ammatory cytokines, reactive oxygen and nitrogen species and proteases, all of which contribute to the atherogenic phenotype in the blood vessel [14]. Invasion of the atherosclerotic plaque by CD4+ T cells also contributes to vascular pathology by recognizing epitopes of various molecules, including oxidized LDL, and by secreting IFN-γ, which then leads to increased infl ammatory cytokine production. Th is chronic production of infl ammatory cytokines and proteases may lead to thinning of the plaque wall and eventual rupture, which results in exposure of the blood to phospholipids, tissue factor and platelet-adhesive matrix molecules, eventually promoting thrombosis and acute CVD events [13].
Coupled to this infl ammatory injury, a loss of endo thelial cells can occur, which, if not repaired, leads to increased infl ammatory cell invasion, vascular smooth muscle proliferation and neo-intima formation [15]. Endo thelial cell apoptosis is a phenomenon with poten tially signifi cant deleterious eff ects on vascular health, including loss of nitric oxide, generation of phosphatidyl serine-rich microparticles with signifi cant tissue factor activity, and potential predisposition to acute coronary events [16,17].
Under normal conditions, vascular damage triggers a response leading to an attempt to repair the endothelium. Although our understanding of vascular repair is rapidly evolving, it is still unclear how it occurs. Several groups have proposed that repair of the vasculature occurs primarily by bone marrow-derived endothelial progenitor cells (EPCs) and myelomonocytic circulating angiogenic cells (CACs) [18]. Indeed, decreased numbers or dysfunction of these cell types may contribute to CVD as EPC numbers inversely correlate with CVD risk, time to fi rst CVD event, and in-stent restenosis risk [19,20]. Additionally, functional impairment of EPCs correlates with coronary artery disease risk [21]. Various mechanisms have been implicated in EPC/CAC dysfunction in these conditions, including reactive oxygen species, telomere shortening/senescence and cytokines such as TNF [22][23][24].

Induction of an imbalance of vascular damage and repair by type I IFNs
Patients with SLE have increased numbers of circulating apoptotic endothelial cells, which correlates with endothelial dysfunction and generation of tissue factor [6]. Various soluble adhesion molecules, such as vascular cell adhesion molecule (VCAM), inter-cellular adhesion molecule and E-selectin, which are released after endothelial cell damage, are increased in SLE and correlate with increased coronary calcium scores. Additionally, soluble levels of the antithrombotic endothelial protein C receptor, which is released secondary to infl ammatory activa tion of metalloproteinases, are increased in SLE and correlate with the presence of carotid plaque [25]. Th ese fi ndings suggest that chronic vascular insult and infl ammation may be important for atherosclerotic pathology [26]. Despite evidence that accelerated endothelial cell death occurs in lupus, a phenomenon that should trigger enhanced vascular repair, the latter is signi fi cantly impaired in lupus patients. SLE patients have decreased circulating EPCs/CACs, and those that persist are characterized by increased apoptosis, even during quiescent disease, decreased proangiogenic molecule synthesis, and decreased capacity to incorporate into formed vascular structures and diff erentiate into mature endothelial cells [27,28] (Figure 1). Th us, patients with SLE have compromised repair of the damaged endothelium, likely leading to the establishment of a milieu that promotes the development of plaque.
Our group has proposed that the mechanism by which vascular repair is impaired in SLE is through increased levels and enhanced eff ects of type I IFNs. Human and murine studies from various groups indicate that IFN-α may be crucial in the pathogenesis of SLE. SLE patients have an 'IFN signature' in peripheral blood mononuclear cells, kidneys and other tissues that correlates with disease activity [29], and type I IFN levels are increased in lupus serum [30]. Further, lupus cells appear to be more sensitive to the eff ects of type I IFN [31]. As part of this pathology, we and others have suggested that the development of lupus-related CVD is, at least partially, attributable to IFN-α and, potentially, to other type I IFNs. Our group has reported that dysfunction of EPC/ CAC diff erentiation in SLE is mediated by IFN-α, as neutralization of this cytokine restores a normal EPC/ CAC phenotype [28]. Th is is further reinforced by the observation of abrogated EPC/CAC numbers and function observed in lupus-prone New Zealand black/ New Zealand white F 1 mice, a strain that depends on type I IFNs for disease development. Additionally, non-lupusprone mice EPCs are unable to properly diff erentiate into mature endothelial cells in the presence of IFN-α [32,33].
Th e pathways by which IFN-α mediates aberrant vascular repair may depend on repression of the proangiogenic factors IL-1β and vascular endothelial growth factor and on upregulation of the antiangiogenic IL-1 receptor antagonist. Indeed, addition of recombinant human IL-β to SLE EPC/CAC cultures restores normal endothelial diff erentiation [32]. Further supporting a role for type I IFNs in premature vascular damage in SLE, patients with high type I IFN signatures have decreased endothelial function, as assessed by peripheral arterial tone measurements [34]. Preliminary evidence indicates that type I IFN signatures correlate with carotid IMT in a lupus cohort [35]. Furthermore, there is evidence that an antiangiogenic phenotype is present in patients with SLE, manifested by decreased vascular density and increased vascular rarefaction in renal blood vessels in vivo, associated with upregulation of the IL-1 receptor antagonist and decreased vascular endothelial growth factor in both the kidney and serum [28,36].
Th e cellular source of type I IFNs leading to abnormal vascular repair was recently examined. Depletion of plasma cytoid DCs (the major producers of IFN-α) does not lead to abrogation of abnormal lupus EPC/CAC diff erentiation in culture [37]; therefore, other cellular sources for this cytokine have been sought. Neutrophilspecifi c genes are abundant in peripheral blood mononuclear cell microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions [38,39]. Th e functionality and pathogenicity of these LDGs was recently investigated by our group. Among other fi ndings, these cells are signifi cantly cytotoxic to endothelial cells. In addition, LDGs have the capacity to secrete suffi cient amounts of IFN-α to interfere with vascular repair. LDG depletion from lupus peripheral blood mononuclear cells restores the ability of EPC/CACs to diff erentiate in vitro into endothelial monolayers [37]. Th is suggests that the presence of these abnormal granulocytes contributes to endothelial dys function and vascular damage in SLE.
Th e above fi ndings suggest that abrogation of the aberrant eff ects of type I IFNs in SLE may not only decrease disease activity but also lead to decreases in CVD risk. Future clinical trials should assess this possibility.
Th e potentially deleterious eff ects of type I IFNs in cardiovascular health are also being explored in non-SLE-related atherosclerosis. For example, IFN-α-producing plasmacytoid DCs have been identifi ed in areas of athero matous plaque. IFN-α then activates plaqueresiding CD4+ T cells to increase TNF-related apoptosisinducing ligand (TRAIL) expression, which results in killing of plaque stabilizing cells and a potential increase in the risk of plaque rupture. Additionally, IFN-α sensitizes plaque-residing myeloid DCs, which may result in further infl ammation and plaque destabilization. Th is cytokine appears to synergize with bacterial products (such as lipo polysaccharide) to increase the synthesis of various proinfl ammatory cyto kines and metallo proteinases [40,41]. Th ese fi ndings indicate that type I IFNs could potentially be involved in athero sclerosis development not only in autoimmune disorders but also in the general population in the context of microbial infections. Th is hypothesis merits further investi gation. Additionally, type I IFNs inhibit CRP up regulation [42], which may explain why the CRP response is usually downregulated in SLE fl ares and why it does not appear to correlate well with atherosclerotic burden in this disease [43].

Other cytokines
Th e infl ammatory cytokine TNF-α appears to play an important role in the initiation and perpetuation of atherosclerotic lesions in the general population. It increases the level of adhesion molecules on the surface of vascular endothelium and promotes enhanced levels of chemotactic proteins, which allows for recruitment of monocytes and T cells into the endothelial wall [44]. In SLE, serum TNF-α levels have been reported to be elevated and correlate with coronary calcium scores [26]. TNF-α levels are also increased in SLE patients with CVD compared to those without CVD, and this correlates with altered lipid profi les [45]. Additionally, it has been postulated that elevated levels of TNF-α may increase soluble VCAM-1 in SLE [46]. However, the exact role this cytokine plays in the development of vascular damage in SLE remains unclear.
IFN-γ, secreted by glycolipid-activated invariant natural killer T-cells, may also contribute to a pathogenic role in SLE-related atherosclerosis [47]. Th e anti athero genic cytokine transforming growth factor-β is decreased in SLE and this decrease may potentially play a role in related CVD [48]. Th e cytokine IL-17, which stimulates production of other pro-infl ammatory cytokines, as well as upregulation of chemokines and adhesion molecules, has been linked to atherosclerotic plaque development in nonlupus-prone models. Atherosclerotic-prone mice have reduced plaque burden when transplanted with bone marrow defi cient in the IL-17 receptor [49]. SLE patients have elevated levels of IL-17 and Th 17 cells are expanded in SLE and can induce endothelial adhesion molecule upregulation [50,51]. Th us, there is a theo retical role for Th 17 T cells and IL-17 in the upregulation of infl ammatory mediators and adhesion molecules that contri bute to CVD in SLE. Future studies should address if, indeed, any of these cytokines play a prominent role in vascular damage and atherosclerosis progression in this disease.
Adiponectin is an adipocytokine with potential benefi cial eff ects at sites of blood vessel injury through inhibition of monocyte adhesion to endothelial cells and of migration and proliferation of smooth muscle cells. However, this molecule is increased in lupus serum and independently correlates with augmented severity of carotid plaque, but not coronary calcifi cation, in lupus patients [25,52]. One hypothesis to explain this discrepancy is that chronic vascular damage in SLE leads to positive feedback on adiponectin-secreting cells. While this may lead to increases in levels of this cytokine, its eff ects are blunted at the site of endothelial damage due to the unique infl ammatory milieu in SLE [53]. Supporting a putative protective role for adiponectin in SLEmediated CVD, this molecule is required for the benefi cial eff ects of rosiglitazone on atherosclerosis development in a mouse model of SLE [54].

T cells
Th 1 CD4+ T cells play a pathogenic role in CVD and their diff erentiation is promoted in atherosclerotic lesions by the increased expression of IFN-γ and IL-12 [44]. Recent evidence suggests that these cells may also play a role in SLE-related CVD, as atherosclerosis-prone LDL receptor-defi cient mice have increased vascular infl ammation and CD4+ T cell infi ltration in their plaques after bone marrow transplant with lupus-susceptible cells [55]. As mentioned above, CD4+ T cells increase TRAIL expression when exposed to IFN-α, which can lead to plaque destabilization [41]. A hypothetical role for autoreactive CD4+ T cells in endothelial damage in SLE also exists. SLE autoreactive T cells can kill antigen presenting cells [56]. Endothelial cells have the ability to act as antigen presenting cells upon activation, and research on transplant rejection suggests that graft endothelial cells are activated to a pro-infl ammatory phenotype and killed by host T cells during antigen presentation [57].

Further research into whether inter actions between endothelial cells and SLE autoreactive T cells result in endothelial damage and an increased risk of atherosclerosis should be considered.
Th e roles of other T-cell subsets in atherosclerosis develop ment are being investigated. Invariant natural killer T cells, which recognize glycolipids and increase with the duration of lupus, may be proatherogenic [47]. In addition, whether the abnormalities reported in T regulatory cells in SLE contribute to atherosclerosis develop ment is unknown [58]. A putative role is suggested by the observation that if regulatory T cell function is compromised in mouse models of atherosclerosis, CVD development is signifi cantly more pronounced [59].

Complement and immune complexes
Inhibition of complement regulatory proteins increases atherosclerosis in mice and decreases in the membraneattack complex attenuate atherosclerotic plaque formation [60]. Complement activated by infl ammatory stimuli can interact with immune complexes (ICs), such as seen in SLE, and result in upregulation of endothelial adhesion molecules, including E-selectin and VCAM-1. Th ese molecules may enhance neutrophil recruitment and endothelial damage [61]. High levels of oxidized LDL/β2 glycoprotein 1 complexes and anti-complex IgG or IgM have been reported in SLE. As the titers of these complexes correlate with a number of CVD risk factors [62], it is possible that they could be proatherogenic. Th e complement component C1q has anti-atherosclerotic eff ects by facilitating macrophage clearance of oxidized and acetylated LDL. As C1q defi ciency is linked to SLE predisposition, its absence may also have a potential role in SLE-mediated atherosclerosis [63]. A role for comple ment activation in atherogenesis has been proposed [64], but the exact role this phenomenon plays in premature vascular damage in SLE remains unclear. ICs may also potentially play a role in atherosclerosis development. IC formation in rabbits accelerates dietinduced athero sclerosis, and mice defi cient in IC receptors have limited atherosclerotic development [65].

Lupus-related dyslipidemias
SLE patients have disturbances in lipoprotein levels and their processing in the bloodstream. High density lipoprotein (HDL) is decreased, while LDL, very low density lipoprotein and triglyceride levels are increased. Th ese alterations may be related to abnormal chylomicron processing secondary to low levels of lipoprotein lipase [66]. Additionally, SLE patients have higher levels of pro-infl ammatory HDL, which is unable to protect LDL from oxidation and promotes endothelial injury. Increased pro-infl ammatory HDL in SLE is associated with augmented atherosclerosis [67]. In addition, the lipid profi le of SLE patients may be more susceptible to environmental eff ects. Lupus-prone mice exposed to high-fat chow showed increased pro-infl ammatory HDL and lipid deposition in vessels when compared to nonlupus mice [68]. A high fat diet administered to LDL receptor-defi cient mice, made susceptible to SLE via bone marrow transplantation, resulted in very elevated lipid levels and signifi cant increases in mortality when compared to similar mice fed regular chow [55]. Th us, predisposition to SLE may increase sensitivity to lipid perturbations by diet and other exposures.

Oxidative stress
Endothelial damage and the initiation of the atherogenic cycle may be infl uenced by the redox environment. SLE patients have increased levels of reactive oxygen and nitrogen species and antibodies to resultant protein adducts, which correlate with disease activity and provide an environment for oxidation of lipoproteins and atherosclerosis development [69]. Homocysteine, a molecule with the capacity to increase reactive oxygen species in the bloodstream, is also increased in SLE patients and correlates with carotid IMT and with coronary calcification [5,70,71]. Further, defense mecha nisms against an altered redox environment are decreased in SLE. For example, paraoxonase, an enzyme with antioxidant activity that circulates attached to HDL and prevents LDL oxidation, is decreased in this disease. Th is correlates with the presence of antibodies to HDL and β2glycoprotein and with enhanced atherosclerosis risk [72].

Antiphospholipid antibodies
Th e role of antiphospholipid (APL) antibodies in premature CVD remains a matter of debate. β2-glyco protein I, abundantly found in vascular plaques, has been hypothesized to be protective against athero sclerosis development. Antibodies against this molecule could, in theory, be detrimental to the vessel wall and promote activation of infl ammatory cascades by IC formation [73]. APL antibodies may increase the likelihood of abnormal ankle brachial index and anti-cardiolipin antibody titers correlate with carotid IMT [70,74]. However, a recent study examining fl ow-mediated dilation and EPC numbers in primary APL syndrome (APS) did not detect any diff erence in these early markers of CVD risk compared with age and gender matched healthy controls [75]. Th is supports previous work in which the presence of APL antibodies did not correlate with endothelial dysfunction or carotid IMT in SLE [7,76]. Using cardiac MRI to fi nd evidence of subclinical ischemic disease, 26% of patients with APS had occult myocardial scarring compared to 11% of controls. Th is study, however, enrolled patients with secondary APS from SLE (22% of their APS cohort) and it is unclear whether a signifi cant number of the patients with myocardial damage also had lupus [77]. Th us, the role of APL antibodies in atherosclerosis development in SLE remains unclear. Nevertheless, because of the arterial thrombosis associated with APS itself, there remains a putative role for these antibodies in the triggering of unstable angina and acute coronary syndromes.

Other autoantibodies
Autoantibodies against regulatory proteins in the atherogenic cycle in SLE may potentially contribute to CVD. Antibodies to the anti-atherogenic HDL and one of its components, Apo A-1, are increased in SLE and rise with disease fl ares [78]. SLE patients have increased levels of anti-lipoprotein lipase antibodies. Th ese also increase with disease activity and may contribute to increased levels of triglycerides [79]. Antibodies to endothelial cells are common in SLE and have been proposed to mediate endothelial injury [80]; however, various groups have shown that these antibodies may not correlate with other markers of endothelial dysfunction [81]. Additionally, antibodies to oxidized LDL, lipoprotein lipase, CRP and annexin V may have a putative role in CVD in SLE [82,83]. Antibodies to heat shock proteins enhance atherosclerotic development in various non-lupus models and are increased in SLE serum [84,85]. Whether this class of antibodies contributes specifi cally to SLE-related atherosclerosis is unknown.

Preventive measures for cardiovascular disease in SLE
Various studies indicate that early and appropriate treatment of immune dysregulation in SLE could be key to hampering CVD development and progression in SLE.
Patients treated with lower doses of cyclophosphamide, azathioprine or corticosteroids had greater progression of CVD than those treated with higher doses [5]. Further, aortic atherosclerosis risk is lower in SLE patients who have undergone treatment with cyclophosphamide when compared to SLE patients who have not received this medication [9]. Th e role of corticosteroid treatment is complex and poorly understood, with potentially dual eff ects on CVD risk that may depend on dose and time of exposure [8].
While no studies have shown a reduced incidence of CVD in patients taking antimalarials, these drugs have positive eff ects on glucose tolerance, lipid profi les, and thrombosis potential [86]. Studies using surrogate markers for CVD have provided mixed results. Anti malarials were signifi cantly associated with decreased presence of carotid plaque in patients with SLE [87]. A correlation between lack of antimalarial use and increased vascular stiff ness in SLE patients has been demonstrated, but no association between their use and coronary calcifi cation was found [88,89]. A cohort study suggested a clear survival benefi t in SLE patients taking antimalarials, but the mechanisms for this eff ect remain to be determined [90]. Because antimalarials can weakly inhibit IFN-α production through inhibition of IC formation and toll-like receptor-7 and -9 signaling [91], modulation of IFN-α levels with a potential improvement in endothelial function and vascular repair may contri bute to the survival benefi t. More research into the vascular eff ects of antimalarials is needed to understand their benefi ts and whether they have an impact on athero sclerotic development.
Mycophenolate mofetil (MMF), an immunosuppressive medication commonly used in SLE, may be potentially benefi cial in atherosclerosis. MMF has a protective eff ect on the development of both transplant and diet-mediated atherosclerosis in animals and is also benefi cial in preventing coronary pathology in cardiac transplant patients [92]. MMF decreases atherosclerotic plaque infl ammation in patients treated for 2 weeks prior to carotid endarterectomy [93]. Whether this drug has a CVD benefi t in SLE patients remains to be determined, and future studies will hopefully address this question.
Th e role of novel biologics in CVD prevention in SLE remains unknown. Currently, studies targeting type I IFNs, IL-17 and the various anti-B cell therapies are underway in SLE and other diseases. Long-term followup to assess atherosclerosis progression in these groups would be important to identify if favorable eff ects are identifi ed. Given the recent observation that impairment in IL-1 pathways in SLE may mediate abnormal vascular repair in this disease [32], a note of caution is added with regards to the use of anakinra and other anti-IL-1 therapies, particularly in SLE, but also in other diseases where aberrant vasculogenesis is observed.
Other non-disease modifying medications may also have a benefi t in SLE-related CVD. SLE patients have a higher incidence of metabolic syndrome and insulin resistance, and this correlates with increases in homocysteine and high sensitivity CRP [94]. Treatment of insulin-resistant states may improve CVD profi les in SLE. Our group reported that treatment of SLE-prone mice with the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone, which is used to treat type II diabetes in humans, resulted in improved insulin sensitivity, improved endothelial function and restored EPC diff erentiation [94]. Additionally, rosiglitazone, another PPAR-γ agonist, decreased aortic atherosclerosis in lupus-and atherosclerosis-prone Gld.apoeE-/-mice [54]. How this class of medications would benefi t CVD in SLE patients warrants additional studies.
Guidelines for CVD prevention in SLE remain nebulous. Th e latest European League Against Rheumatism (EULAR) recommendations suggest yearly monitoring of traditional and/or non-lupus-specifi c CVD risk factors, including smoking, activity level, oral contraceptive use, hormonal therapies and family history of CVD. Monitoring of blood pressure, lipids and glucose is also recommended [95]. One group has proposed treating SLE as a coronary heart disease equivalent, targeting recommenda tions as suggested by the Adult Treatment Panel guidelines (ATPIII) [96]. However, whether these guidelines will be suffi cient to abrogate CVD risk in SLE remains to be determined. Th e use of statins in SLE has not been systematically or extensively studied, but they have been shown to improve endothelium-dependent fl ow-mediated dilation and possibly slow progression of carotid IMT in adult lupus as well as increase EPC numbers in other conditions, including diabetes mellitus [97][98][99]. While trending toward a protective eff ect for carotid IMT thickness in pediatric SLE, prophylactic statin use in children did not show a statistically significant diff erence compared to placebo [100]. A murine lupus/atherosclerosis model displayed decreased atherosclerosis and amelioration of renal disease when treated with simvastatin [101]. Statins can also block IFN-α production in peripheral blood from healthy controls in response to exposure to SLE patients' serum. Th is blockade occurs through inhibition of the Rho kinase, likely in plasmacytoid DCs [102]. Future research will hopefully clarify the role of statin use in SLE patients.
Finally, diet may be an important modifi able risk factor that can alter predisposition to atherosclerotic lesions. LDL receptor-defi cient mice that underwent bone marrow transplant with SLE-prone cells had increased sensitivity to dietary fat. A Western-style diet containing 21% fat increased atherosclerotic lesions, pathogenic antibody formation and severity of renal disease when compared to mice fed a regular diet [55]. A diff erent model of lupus-prone mice fed high-fat chow or administered leptin had accelerated and increased proteinuria, suggesting an interplay between diet and lupus [68]. Certainly, some murine lupus models have decreased life spans when fed a high-fat diet [103]. Th us, further understanding of the role of diet on immune modulation and CVD risk in SLE may be key in vascular damage prevention.

Conclusion
Th e CVD risk in SLE patients stems from a combination of traditional risk factors and SLE-specifi c mechanisms that incorporate chronic infl ammation, endothelial dysfunction, decreased vascular repair through a type I IFN eff ect, antibody formation and perturbed lipid homeo stasis and redox environment (Figure 2). Continued research into the mechanisms of lupus-related CVD will hopefully provide eff ective tools and targets to improve their survival and overall quality of life.
Additionally, it is crucial that future clinical trials in SLE include biomarkers of vascular damage, functional studies of vascular health and assessment of subclinical and clinical CVD as endpoints in their effi cacy analysis.

Figure 2. The interplay of various infl ammatory mediators increases vascular damage and plaque formation in systemic lupus
erythematosus. IFN-α contributes to endothelial dysfunction and decreased repair of endothelial damage by decreasing numbers and function of endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). In addition to synthesizing type I IFNs, low density granulocytes (LDGs) present in systemic lupus erythematosus patients are directly toxic to the endothelium. Altered lipid profi les secondary to abnormal chylomicron processing, increased pro-infl ammatory high density lipoprotein (pi-HDL) and increased oxidized low density lipoprotein (ox-LDL) also promote atherosclerosis development. The abnormal redox environment in systemic lupus erythematosus also promotes endothelial dysfunction and modulates lipid profi les. Antibodies to lipoproteins or endothelial targets may also contribute to vascular damage. Cytokines such as TNF-α, IL-17 and IFN-γ may also have pro-atherogenic eff ects on blood vessels. The combination of some or all of these factors in an individual patient results in endothelial dysfunction, increased plaque burden and an increased risk of cardiovascular events. IC, immune complex; PDC, plasmacytoid dendritic cell; RNS, reactive nitrogen species; ROS, reactive oxygen species.