Impaired metabolism predicts coronary artery calcification in women with systemic lupus erythematosus

Abstract

Background: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD.

Methods: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD).

Findings: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE.

Interpretation: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE.

Funding: INSERM and Sorbonne Université.

Keywords: Cardiovascular diseases; Ceramides; Lipidomics; Metabolomics; Systemic lupus erythematosus.

Fig. 1

Analysis of the circulating lipidome according to the coronary artery calcium in women with SLE. Lipidomic profiling was performed in sera by LC-ESI-MS/MS. Heat map showing lipid species distribution according to coronary artery calcium (CAC) scores (a, d) or to the presence or absence of coronary calcium (b). Forest plot of individual lipid species in women with SLE with or without coronary calcium (c). n = 211 women with SLE. Data are means ± SEM. Groups were compared using student's test, p value < 0.05 corrected for FDR. Low (CAC = 0, n = 141), moderate (0 < CAC < 100, n = 48) and high (CAC ≥ 100, n = 22).

Fig. 2

Analysis of the circulating metabolome according to the coronary artery calcium in women with SLE. Metabolomic profiling was performed in sera by LC-HRMS. Heat map showing metabolites distribution according to coronary artery calcium (CAC) scores (a, e) or to the presence or absence of coronary calcium (c). Forest plot of metabolites in women with SLE according to the presence or the absence of coronary calcium (b) or coronary artery calcium (CAC) scores (d). n = 211 women with SLE. Data are means ± SEM. Groups were compared using student's test, p value < 0.05 corrected for FDR. Low (CAC = 0, n = 141), moderate (0 < CAC < 100, n = 48) and high (CAC ≥ 100, n = 22).

Fig. 3

Prediction scores for the presence of coronary artery calcium in women in SLE. Receiver operating characteristic (ROC) curves noting the incremental value of lipidomic and metabolomic scores upon clinical-biological score for the prediction of the presence of coronary artery calcium in women with SLE. Developed prognostic scores were plotted on an AUC-ROC curve and validated by random forest machine learning algorithm. AUC, area under the curve; ROC, receiver operating characteristic.