Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients

Abstract

Aims Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. Methods and results Ceramides and PCs were analysed using liquid chromatography–mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28–1.63) in WECAC, 1.47 (1.34–1.61) in the LIPID trial, and 1.69 (1.31–2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44–1.85) and 2.04 (1.57–2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. Conclusion A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification

“…The original CERT1 score contained three single ceramides and three ceramide/ceramide ratios, whereas the CERT2 score had one ceramide/ceramide ratio, two ceramide/PC ratios and a single PC. Ceramide-PC ratio components of the CERT2 test showed higher HRs than the previously published ceramide–ceramide ratios, across all three studies ( 14 ).…”

“… Calculation of CERT2 risk scores and determination of CVD risk groups ( 14 ). When determining the score for a subject, it is evaluated to which quartile the person belongs with regards to each score component.…”

“…Main drivers of the lipid species choice were analytical stability, ability to incorporate into the existing CERT1 assay, and statistical strength across a number of clinical cohorts. The novel ceramide test score, named CERT2, was developed in the WECAC study and validated in the LIPID and KAROLA studies, by selecting the test components in a stepwise manner ( 14 ). The original CERT1 score contained three single ceramides and three ceramide/ceramide ratios, whereas the CERT2 score had one ceramide/ceramide ratio, two ceramide/PC ratios and a single PC.…”

“…The CERT2 risk estimation tool showed improved performance metrics and can be used to reliably stratify CHD patients for their risk of CV events, especially CV death ( 14 ). The performance of the CERT2 score, in addition to other CV biomarkers, was evaluated in three independent large cohorts of CHD patients.…”

A lipid atlas of human carotid atherosclerosis

“…In literature, high levels of ceramides in serum, lipids that are structurally-related to SMs, have been associated with high-risk plaque 30,31 . We detected low levels of ceramides in CEA tissue in the mass identification measurement using the Lipidyzer platform, but ceramide levels were probably under the detection limit of the MALDI-MSI experiments in this study or were suppressed by other ions.…”