Web:	mayocliniclabs.com
Email:	mcl@mayo.edu
Telephone:	800-533-1710
International:	+1 855-379-3115
Values are valid only on day of printing

June 2023 – Clinical Chemistry

By MCL Education • June 9, 2023

A 62-year-old woman has been diagnosed with hyperlipidemia for six years. She has a strong family history of high cholesterol, a lipid profile suggestive of familial hypercholesterolemia, but is negative on genetic testing. Patient has no prior history of hypertension or diabetes, is an active smoker, and her estimated 10-year risk for atherosclerotic cardiovascular disease (ASCVD) was 8.6% [Statin Choice Decision AID - Site (mayoclinic.org)]. Previous trials of lipid lowering medications were unsuccessful due to statin-induced myalgias.

Patient had an emergency department visit for chest pain. An electrocardiogram and troponin panel ruled out myocardial infarction. Plasma ceramides, CT imaging, and cardio-stress test were ordered in follow-up.

Based on these findings, how does ceramide testing help with cardiovascular disease risk management for this patient?

Ceramide is the same risk marker as LDL-cholesterol; do not provide additional information for predicting risk.
Patient at moderate risk; no additional intervention recommended.
Patient at high risk; may benefit from aggressive treatment and lifestyle changes.
Patient at low risk; no additional intervention recommended.

The correct answer is ...

Patient at high risk; may benefit from aggressive treatment and lifestyle changes.

Ceramides are bioactive lipids produced in all cells and tissues. They act as secondary messengers for cell signaling and are involved in apoptosis, inflammation, obesity, and insulin resistance. Testing circulating plasma ceramides can be clinically useful in many ways, including: a) identifying patient with high-risk coronary heart disease, who might benefit from more intense medical intervention; b) assessing risk of patients with intermediate cardiovascular risk based on conventional lipids; c) assessing treatment response and motivating patient compliance to therapy and lifestyle changes.^1-3

How are ceramides associated with coronary heart disease?

Ceramides are independent risk markers for predicting negative cardiovascular outcomes.⁴ Certain ceramide species have a strong association with atherosclerotic cardiovascular disease (ASCVD), elevated ceramides associated with increased risk, and poor clinical outcomes (such as fatal myocardial infarction and cardiovascular mortality). These have been supported by numerous case-control, large-scale population studies, and randomized clinical trials.^2,3,5 Ceramides including N-palmitory-sphingosine (Cer16:0), N stearoyl-sphingosine (Cer18:0), and N nervonoyl-sphingosine (Cer24:1) are linked with cardiovascular mortality. Hazard ratios for Cer16:0, Cer18:0, Cer24:1, and ASCVD outcomes from different studies ranged from 1.1 (95%CI, 1.02, 1.21) to 4.49 (95% CI, 2.24 -8.99), and multivariate analysis shows lack of association with LDL-cholesterol concentration and other traditional risk factors.² These indicate ceramides provide independent risk stratification for cardiovascular disease beyond LDL-cholesterol.

Ceramide risk score: what is it?

Individual ceramide species have specific physiological functions. Furthermore, individual ceramide species vary widely in their relative serum concentrations between individuals. This complexity hinders direct clinical interpretation for a given ceramide in isolation.³ The MI-Heart Ceramide risk score measures four ceramides and weighs their contribution to ASCVD risk to provide a simple and readily communicated result.^4,6 This approach has been validated in a large-scale, population-based study of more than 8,000 healthy individuals⁷ and a Mayo Clinic study in an >1,000 angiography cohort,³ which showed that a patient at high-risk category has a 1.5- to 4.2-fold increased risk for major adverse cardiovascular events (MACE) and MACE death compared with a low-risk group.^3,7

Follow-up

Ceramides suggested the patient was high-risk for ASCVD despite the intermediate risk calculated. Imaging studies confirmed mild coronary blockage with high-risk of ASCVD events. The patient elected to begin aggressive lipid lowering treatment (PCSK9-inhibitor) and lifestyle changes (smoking cessation, Mediterranean diet, and increased exercise). Ceramides and traditional lipids normalized over 18 months.

References

Hilvo M, Vasile VC, Donato LJ, Hurme R, Laaksonen R. Ceramides and ceramide scores: clinical applications for cardiometabolic risk stratification. Front Endocrinol (Lausanne). 2020 Sep 29;11:570628. doi:10.3389/fendo.2020.570628.
Meeusen JW, Donato LJ, Kopecky SL, Vasile VC, Jaffe AS, Laaksonen R. Ceramides improve atherosclerotic cardiovascular disease risk assessment beyond standard risk factors. Clin Chim Acta. 2020 Dec;511:138-142. doi: 10.1016/j.cca.2020.10.005.
Vasile VC, Meeusen JW, Medina Inojosa JR, et al. Ceramide scores predict cardiovascular risk in the community. Arterioscler. Thromb. Vasc. Biol. 2021. 41(4): p.1558-1569.
Laaksonen R., Ekroos K, Sysi-Aho M, et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. Eur Heart J. 2016. 37(25): p.1967-1976.
Hilvo M, Meikle PJ, Pedersen ER, et al. Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients. Eur Heart J. 2020. 41(3): p. 371-380. doi:10.1093/eurheartj/ehz387.
Nicholls, M. Plasma ceramides and cardiac risk. Eur Heart J. 2017. 38(18): p. 1359-1360.
Havulinna AS, Sysi-Aho M, Hilvo M, et al. Circulating ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 cohort. Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2424-2430. doi:10.1161/ATVBAHA.116.307497.