Ceramides improve cardiovascular risk prediction beyond low-density lipoprotein cholesterol
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Updated: Jul 4, 2025
Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein
Published on: October 12, 2017
Andreas Leiherer1,2,3, Axel Muendlein1,2, Christoph H Saely1,2,4
1Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Carinagasse 47, A-6800 Feldkirch, Austria.
Insights
Low-density lipoprotein cholesterol (LDL-C) is a poor predictor of cardiovascular risk in older patients. Ceramides and phosphatidylcholines offer more accurate risk prediction in high-risk individuals.
Area of Science:
- Cardiovascular Medicine
- Lipidology
- Biomarker Discovery
Background:
- Low-density lipoprotein cholesterol (LDL-C) is a primary cardiovascular risk predictor but its accuracy is limited in elderly patients and those with comorbidities or on medication.
- U-shaped or inverse associations between LDL-C and mortality are common in such patient groups, questioning its predictive power.
- The applicability of these limitations to other lipid markers, specifically ceramides and phosphatidylcholines, remains unclear.
Purpose of the Study:
- To investigate whether ceramides and phosphatidylcholines, unlike LDL-C, can accurately predict cardiovascular risk in high-risk patient cohorts.
- To compare the predictive capabilities of LDL-C, ceramides, and phosphatidylcholines in patients undergoing coronary angiography or diagnosed with peripheral artery disease.
Main Methods:
- An observational cohort study involving 1195 high-risk patients (median age 67 years) with up to 16 years of follow-up.
- Data collection included cardiovascular mortality, baseline lipid profiles (including LDL-C, ceramides, and phosphatidylcholines), and medication status (51% on statins).
- Statistical analyses included Cox regression to assess the association between lipid markers and cardiovascular mortality, adjusting for covariates.
Main Results:
- A U-shaped association was observed between LDL-C and cardiovascular mortality, with a trough around 150 mg/dL, indicating limited predictive value.
- LDL-C and other cholesterol species failed to predict cardiovascular risk in Cox regression analyses.
- Ceramide- and phosphatidylcholine-based markers demonstrated a linear association with cardiovascular risk and were significant predictors, even after multivariate adjustment.
Conclusions:
- Ceramide- and phosphatidylcholine-based markers show superior cardiovascular risk prediction compared to LDL-C in high-risk patient populations.
- These lipid markers may serve as more accurate tools for risk stratification in individuals with established cardiovascular disease or high risk.
- Future research should focus on validating these novel lipid biomarkers for clinical application in cardiovascular risk assessment.
Aims:
Low-density lipoprotein 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.
Methods And Results:
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 of 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 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.
Conclusion:
We thus suggest that ceramides- and phosphatidylcholine-based predictors rather than LDL-C may be used for a more accurate cardiovascular risk prediction in high-risk patients.
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