Cardiovascular Disease in Systemic Lupus Erythematosus: An Update

Yudong Liu; Mariana J. Kaplan


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

In This Article

Recent Advances in Pathogenesis of Premature Atherosclerosis in Systemic Lupus Erythematosus

Vascular Damage and Cardiovascular Disease in Systemic Lupus Erythematosus

Endothelial dysfunction is one of the first recognized steps leading to established CVD. A recent study reported a high rate of endothelial dysfunction in individuals with recent onset of SLE (<5 years), even those with mild disease activity and without traditional CVD risk factors.[14] Various soluble adhesion molecules, such as vascular cell adhesion molecule, which are released after endothelial cell damage and have been proposed as markers of endothelial dysfunction, are increased in SLE and correlate with higher coronary calcium scores.[15] Nhek et al.[16] recently showed that SLE sera can induce platelet activation leading to endothelial cell activation and synthesis of proinflammatory mediators in an IL-1-dependent manner (Figure 1). A profound imbalance between endothelial cell damage and repair has been identified in SLE.[17] Thus, patients with SLE have impaired endothelial cell and compromised repair of the damaged endothelial cells, which may promote the development of vascular plaque.

Figure 1.

Recent developments in the understanding of the mechanisms of vascular risk in SLE. A number of pathogenic mechanisms contribute to the accelerated atheroclerosis and vascular injury in SLE and were recently highlighted. aβ2-GPI, antiβ2-glycoprotein I antibodies; CCL, C-C Motif Chemokine Ligand; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; HDL, high-density lipoprotein; ICAM, intercellular adhesion molecule 1; IgM anti-PC, IgM antibodies against phosphorylcholine; ICs, immune complex; iTCR, invariant TCR; LDL, low-density lipoprotein; NETs, neutrophil extracellular traps; oxLDL, oxidized LDL; pDCs, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; VE-cadherin, vascular endothelial cadherin.

Arterial stiffness, as a marker of subclinical atherosclerosis, is significantly elevated in patients with SLE. A low level of cardiorespiratory fitness (CRF) has been shown to associate with the risk of CVD in the general population.[18] A recent study examined the association of CRF with arterial stiffness in SLE. CRF was inversely associated with pulse wave velocity (PWV), a marker for arterial stiffness,[19,20] suggesting that CRF may attenuate the age-related arterial stiffening in SLE and contribute to primary prevention of CVD in SLE.[20] In contrast, a recent meta-analysis failed to show significant effects of exercise on CVD risk factors and disease activity, but reported that exercise improves cardiorespiratory capacity and reduces fatigue in SLE.[21] By utilizing PWV as a marker of arterial stiffness, Castejon et al.[22] reported that SLE patients with metabolic syndrome display increased arterial stiffness, which is associated with a decreased percentage of circulating endothelial progenitor cells (EPCs). In contrast, a recent study failed to demonstrate an association between EPC colonies, percentages of circulating EPCs, or SLE disease activity index with PWV.[23] These results indicate that additional longitudinal studies in larger cohorts of SLE patients are needed to conclusively assess the role of various biomarkers in vascular dysfunction in this patient population.

Dysregulation of the Innate Immune Response and Systemic Lupus Erythematosus-related Cardiovascular Disease

Owing to the central role of type I interferons (IFNs) in SLE, these cytokines have been extensively investigated as a contributing factor to the development of lupus-related CVD. Lupus patients with a high type I IFN signature have decreased endothelial function.[24] Enhanced serum IFN activity has been significantly associated with decreased endothelial function, whereas factors such as serum levels of high-sensitivity CRP, adhesion molecules, and lupus disease activity are not. This suggests that enhanced type I IFN signaling may be particularly important in driving increased CV risk in SLE.[25] Tyden et al.[26] recently reported that activation of the type I IFN system in SLE may impair endothelial function even in those lupus patients with low disease activity. Diminished activity of endothelial nitric oxide synthase (eNOS) and loss of nitric oxide production are critical in the development of endothelial dysfunction. One of the detrimental effects of IFN-α on endothelial dysfunction was recently reported by Buie et al.[27] as this cytokine was reported to inhibit eNOS expression at the mRNA and protein levels and to impair insulin-mediated nitric oxide production in endothelial cells (Figure 1). In addition, a recent study demonstrated that diet-induced insulin resistance is initiated by a type I IFN response that triggers accumulation of cluster of differentiation (CD)8+ T cells in the liver, resulting in glucose dysregulation and hepatic inflammation.[28] The pathogenic role of type I IFNs is also observed in the case of MI. King et al.[29] recently showed that ischemic cell death and uptake of cell debris by macrophages in the heart fuels a fatal response to MI by activating interferon regulatory factor 3 and type I IFN production through cyclic GMP-AMP synthase-stimulator of IFN genes. Further, treatment of mice with an type I Interferon receptor-neutralizing antibody after MI ablated the IFN response and improved left ventricular dysfunction and survival.[29]

A distinct subset of proinflammatory neutrophils present in lupus patients, called low-density granulocytes (LDGs), have been proposed to play pathogenic roles in lupus CVD by a variety of mechanisms, including their enhanced propensity to form neutrophil extracellular traps (NETs).[30] A recent publication reported that NETs promote vascular leakage and endothelial-to-mesenchymal transition through the degradation of vascular endothelial cadherin and subsequent activation of β-catenin signaling, and this may promote endothelial dysfunction (Figure 1).[31] Carlucci et al.[32] recently reported that SLE patients with overall mild-moderate disease activity display a significant increase in aortic wall inflammation, as assessed by[18F]-Fluorodeoxyglucose-PET/computed tomography scan, when compared with healthy controls. This same SLE cohort displayed a significant increase in noncalcified coronary plaque burden (NCB) and endothelial dysfunction. When analyzing the associations of lupus-related factors to these vascular abnormalities, the level of LDGs was independently associated with NCB.[32] In addition, an LDG gene signature obtained by RNA sequencing showed a significant association with the presence of high vascular inflammation and high NCB in SLE.[32] These results support the notion that aberrant neutrophil biology contributes to the development of premature vascular disease in SLE.