Cardiovascular Disease in Systemic Lupus Erythematosus: An Update

Yudong Liu; Mariana J. Kaplan

Disclosures

Curr Opin Rheumatol. 2018;30(5):441-448. 

In This Article

Dysregulation of Adaptive Immune Responses and Systemic Lupus Erythematosus-related Cardiovascular Disease

T Cells

As T cells play a critical role in both atherosclerosis and SLE, dysregulated T cells may contribute to SLE-associated CVD and this is also supported by animal models.[33] In patients with SLE, plasmacytoid dendritic cells induce the expansion of CXC chemokine receptor 3+ CD4+ T cells and their migration from the bloodstream into the arterial wall, where they may play proatherogenic roles.[34] The role of IL-17A in atherosclerosis development in SLE is unknown, but low-density lipoprotein receptor knockout mice that receive transfer of CD4+ T cells from SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice develop accelerated atherosclerosis because of an imbalance between IL-17 production and Treg function.[35] In a recent prospective 5-year study, increased levels of CD4+CC chemokine receptor (CCR)5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients.[4] In a recent murine atherosclerosis study, CCR5 was reported to be critical for the homing of CD4+ T cells into the atherosclerotic plaque.[36] These findings support the possibility that increased levels of CD4+CCR5+ T cells in SLE may contribute to atherogenesis.

A recent study suggests that invariant natural killer T (iNKT) cells may promote an atheroprotective effect in SLE patients with asymptomatic atherosclerotic plaques.[37] The authors found that healthy iNKT cells differentiated in the presence of healthy monocytes and serum from SLE patients with asymptomatic plaque polarized macrophages toward an anti-inflammatory M2 phenotype, whereas SLE patients with clinical CVD had unresponsive iNKT cells and increased proinflammatory monocytes.[37] Furthermore, the authors demonstrated that the anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes (Figure 1).[37]

Autoantibodies and Immune Complexes

Autoantibodies and immune complexes (ICs) may also contribute to vascular damage and atherosclerosis development in SLE. IgG antioxidized (ox) LDL (oxLDL) ICs are present in both rabbit and human atherosclerotic lesions.[38] In SLE, IgG anti oxLDL Abs are significantly elevated.[39] Stimulation of bone marrow-derived dendritic cells (BMDCs) with oxLDL ICs leads to enhanced secretion of IL-1β, a cytokine important in atherogenesis and inflammasome activation, whereas BMDCs stimulated with free oxLDL promote enhanced Th17 polarization (Figure 1).[40]

aPL antibodies, including lupus anticoagulant, anticardiolipin antibodies and antiβ2-glycoprotein I antibodies (aβ2-GPI), are present in 20–30% of SLE patients and have been linked to an increased risk of venous and arterial thrombosis.[41] A significant percentage of SLE patients show a β2-GPI-specific T cell reactivity, which is associated with subclinical atherosclerosis.[42] β2-GPI binds to oxLDL to form oxLDL/β2-GPI complexes[43] that can increase foam cell formation and proinflammatory cytokine and chemokine expression.[44] Increases in oxLDL/β2-GPI and oxLDL/β2-GPI/aβ2-GPI complexes have been reported in SLE, and correlate with several CVD risk factors (Figure 1).[45] In contrast, immunoglobulin M (IgM) antibodies recognizing phosphorylcholine, may exert protective roles in CVD in SLE, at least in part by promoting Treg polarization and reducing the production of IL-17 and tumor necrosis factor (TNF)-α (Figure 1).[46]

Dyslipidemia in Systemic Lupus Erythematosus

Dyslipidemia is a hallmark of atherosclerosis and CVD. In SLE, dyslipidemia is characterized by elevations in total cholesterol, LDL, triglycerides, and apolipoprotein B, and a reduction in high-density lipoprotein (HDL).[47] This pattern is often observed at the time of lupus diagnosis and correlates to SLE activity.[48] SLE patients display increased levels of oxidized and dysfunctional HDL with impaired cholesterol efflux capacity and in association with atherosclerosis.[49–51] Mechanistically, HDL exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to downregulation of Toll-like receptor (TLR)-induced inflammatory responses.[52] In contrast, a recent study reported that oxidized lupus HDL promotes proinflammatory responses in macrophages.[53] Indeed, SLE HDL activates nuclear factor (NF)κB, promotes inflammatory cytokine production, and fails to block TLR-induced inflammation. This failure of lupus HDL to block inflammatory responses is because of an impaired ability to promote ATF3 synthesis and its nuclear translocation and this was driven by signaling through the oxidized LDL receptor (Figure 1).[53] Indeed, an HDL mimetic given to lupus-prone mice systemically promoted significant ATF3 induction and decreases in proinflammatory cytokine levels, supporting a putative therapeutic potential.[53] NETs were previously reported to have the ability to oxidized HDL in a region-specific proatherogenic manner that impairs the cholesterol efflux capacity of HDL.[49] In a recent study, impairments in cholesterol efflux capacity were significantly associated with vascular inflammation and NCB in multivariate analysis, suggesting that therapeutic strategies that improve HDL function may have significant cardioprotective effects in SLE.[32]

Insulin Resistance

Insulin resistance has been shown to contribute to CVD in SLE. A recent study assessed insulin sensitivity in SLE patients in response to a meal tolerance test. SLE patients displayed a bi-hormone metabolic abnormality characterized by increased insulin resistance and hyperglucagonemia despite normal glucose tolerance and preserved ß-cell function and skeletal muscle glucose transporter 4 translocation. The authors thus propose that strategies capable of ameliorating insulin sensitivity may require more than targeting insulin resistance alone.[54]

Screening and Assessing Cardiovascular Disease in Systemic Lupus Erythematosus

Mavrogeni et al.[55] recently demonstrated that CV magnetic resonance can detect silent heart disease missed by echocardiography. Indeed, CV magnetic resonance detected abnormalities in 27.5% of SLE patients who presented normal echocardiography but had silent/past myocarditis, MI, or vasculitis.[55] Visceral adipose tissue correlates with CV risk factors. A recent study reveals that SLE is associated with increased visceral adipose tissue and altered adiposity distribution..[56] Furthermore, aortic perivascular adipose tissue density associated with aortic calcification in SLE women, indicating that adipose tissue dysfunction may contribute to CVD in SLE.[57]

Osteoprotegerin and osteopontin (OPN) are involved in vascular calcification and are upregulated in symptomatic human carotid atherosclerosis.[58] A recent study reported that serum OPN levels are significantly increased in SLE compared with healthy controls, particularly in those patients with lupus nephritis..[59] OPN levels were significantly associated with CV events, indicating that this molecule may contribute to SLE CVD and could potentially serve as a biomarker of CV risk in this patient population.[59] In another study, although SLE patients with higher osteoprotegerin levels had higher measures of coronary artery calcium, carotid intima media thickness, and more carotid plaque, no statistically significant associations were noted after adjustment for age.[60] In addition, a recent study shows that biomarkers reflecting receptor-activated apoptosis and tissue degradation, including Fas, TNF receptor 1, TNF-related apoptosis inducing ligand receptor 2, matrix metalloproteinase-1, and matrix metalloproteinase-7, are significantly elevated in SLE patients with CVD than those without CVD.[61]

Impairment of total antioxidant capacity is associated with subclinical coronary microvascular dysfunction in SLE patients without traditional CV risk factors.[62] Paraoxonase1 (PON1), an enzyme with antioxidant activity that attaches to HDL and can prevent oxidative modifications of LDL,[63] is decreased in SLE and is associated with vascular damage.[64] A recent study evaluated the role of anti-PON1 and anti-HDL antibodies as biomarkers of lupus CVD. They found that anti-HDL antibodies were significantly associated with higher risk of CVD, and anti-PON1 antibodies were significantly associated with carotid intima media thickness in SLE.[65] Thus, those antibodies could be potential early biomarkers of premature atherosclerosis in SLE.

Cardiac troponin T (cTnT) has been proposed as a marker of myocyte necrosis and injury in the early phases of acute MI.[66] High-sensitivity cTnT has shown promising value in predicting CVD in the general population with apparent low CVD risk.[67] In a recent cross-sectional controlled study, Divard et al.[68] reported that levels of high-sensitivity cTnT were independently associated with subclinical atherosclerosis in asymptomatic SLE patients considered at low risk for CVD based on traditional risk factors.

As mentioned previously, LDGs play pathogenic roles in lupus CVD. A recent study demonstrated that LDG levels were significantly associated with NCB severity and lower cholesterol efflux capacity in SLE in an unadjusted linear regression analysis.[32] Furthermore, the authors found that a neutrophil gene signature was significantly associated with vascular disease in SLE. Indeed, some of the most upregulated genes in the high-NCB SLE groups were the genes previously found to be upregulated in LDGs when compared with normal density neutrophils.[32] Those findings suggest that the levels of LDGs may serve as a marker for CVD risk in SLE.

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