Ceramides improve cardiovascular risk prediction beyond LDL-cholesterol

LDL-cholesterol (LDL-C) is the best documented cardiovascular risk predictor and at the same time serves as a target for lipid-lowering therapy. However, the power of LDL-C to predict risk is biased by advanced age, comorbidities, and medical treatment, all known to impact cholesterol levels. Consequently, such biased patient cohorts often feature a U-shaped or inverse association between LDL-C and cardiovascular or overall mortality. It is not clear whether these constraints for risk prediction may likewise apply to other lipid risk markers in particular to ceramides and phosphatidylcholines. In this observational cohort study, we recorded cardiovascular mortality in 1195 patients over a period of up to 16 years, comprising a total of 12.262 patient-years. The median age of patients at baseline was 67 years. All participants were either consecutively referred to elective coronary angiography or diagnosed with peripheral artery disease, indicating a high cardiovascular risk. At baseline, 51% of the patients were under statin therapy. We found a U-shaped association between LDL-C and cardiovascular mortality with a trough level around 150 mg/dL of LDL-C. Cox regression analyses revealed that LDL-C and other cholesterol species failed to predict cardiovascular risk. In contrast, no U-shaped but a linear association was found for ceramide- and phosphatidylcholine-containing markers and these markers were able to significantly predict the cardiovascular risk even after multivariate adjustment. We thus suggest that ceramides- and phosphatidylcholine-based predictors rather than LDL-C can be used for a more accurate cardiovascular risk prediction in high-risk patients.