Research Article: Sphingolipid–renal interplay in coronary artery calcification: ceramide profiling and imaging validation from the CRUISE-MET study
Abstract:
Coronary artery calcification (CAC) represents a distinct imaging phenotype reflecting advanced vascular remodeling, particularly in patients with chronic kidney disease (CKD). However, metabolic determinants linking renal dysfunction to CAC remain incompletely understood. Ceramides, bioactive sphingolipids involved in vascular inflammation and calcification, may represent potential mediators of this interaction.
In this cross-sectional analysis of 851 coronary artery disease (CAD) patients from the CRUISE-MET trial (NCT06383208), six plasma ceramide species [Cer(18:1/16:0), (18:1/18:0), (18:1/20:0), (18:1/22:0), (18:1/24:0), and (18:1/24:1)] were quantified by UHPLC–MS/MS. CAC severity was classified angiographically as absent, mild, moderate, or severe. Logistic regression, ROC analysis, and restricted cubic splines assessed associations. Joint and mediation analyses examined interactions with CKD. Sensitivity analyses evaluated consistency across subgroups and in a cohort with non-ECG-gated chest CT–derived CAC scores.
Patients with moderate-to-severe CAC had higher Cer(18:1/16:0), Cer(18:1/24:1), older age, higher SYNTAX scores, and lower estimated glomerular filtration rate (eGFR) (all p<0.05). Each SD increase in Cer(18:1/16:0) was associated with 59% higher odds of moderate-to-severe CAC (OR = 1.59, 95% CI: 1.33–1.88, p<0.001); the highest tertile was associated with 151% higher odds (OR = 2.51, 95% CI: 1.68–3.75, p<0.001). CKD modified this association (p for interaction=0.032), with coexisting CKD and high ceramide exposure yielding nearly fourfold higher odds (OR = 3.94, 95% CI: 2.47–6.28, p<0.001). Mediation analysis indicated Cer(18:1/16:0) accounted for 15.6% of the CKD–CAC association. Associations remained directionally consistent across sensitivity analyses. In the CT subgroup, modest associations were observed between selected ceramide species and quantitative CACS.
Specific ceramides, particularly Cer(18:1/16:0), are independently associated with CAC severity, with stronger associations observed in patients with CKD.
Introduction:
Coronary artery calcification (CAC) represents a distinct imaging phenotype reflecting advanced vascular remodeling, particularly in patients with chronic kidney disease (CKD). However, metabolic determinants linking renal dysfunction to CAC remain incompletely understood. Ceramides, bioactive sphingolipids involved in vascular inflammation and calcification, may represent potential mediators of this interaction.
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