Plasma Ceramides Predict Cardiovascular Death in Patients With Stable Coronary Artery Disease and Acute Coronary Syndromes Beyond LDL-Cholesterol

Reijo Laaksonen; Kim Ekroos; Marko Sysi-Aho; Mika Hilvo; Terhi Vihervaara; Dimple Kauhanen; Matti Suoniemi; Reini Hurme; Winfried März; Hubert Scharnagl; Tatjana Stojakovic; Efthymia Vlachopoulou; Marja-Liisa Lokki; Markku S. Nieminen; Roland Klingenberg; Christian M. Matter; Thorsten Hornemann; Peter Jüni; Nicolas Rodondi; Lorenz Räber; StephanWindecker; Baris Gencer; Eva Ringdal Pedersen; Grethe S. Tell; Ottar Nygå rd; Francois Mach; Juha Sinisalo; Thomas F. Lüscher


Eur Heart J. 2016;37(25):1967-1976. 

In This Article

Abstract and Introduction


Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts.

Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine—Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02).

Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.


Given the high prevalence of coronary artery disease (CAD) and associated mortality, prevention of fatal and non-fatal myocardial infarctions (MI) in CAD patients remains an ongoing clinical challenge. Mortality rates among stable CAD patients range between 1% and 3%, while rates of non-fatal events are 1–2% annually.[1] In patients with acute coronary syndromes (ACS) who survive the acute event, the rate of MI and death is markedly higher, particularly during the first year.[2] However, at the individual level, the event risk may vary considerably, which makes risk estimation tools necessary to improve patient management. Expedient risk stratification should identify individuals at risk requiring more intensive therapy. Conversely, patients with a favorable prognosis should be identified to avoid drug overuse and associated side effects.[3]

Hypothesis free lipidomic analyses have revealed a handful of lipids potentially qualifying as useful prognostic markers for CAD.[4–6] In our initial lipidomic study, distinct ceramide species were significantly associated with CVD among CAD patients.[4] Molecular lipid species, particularly ceramide(d18:1/16:0), were also associated with necrotic core tissue type and lipid core burden in coronary angiography, and were predictive for 1-year clinical outcome in 581 ACS and stable CAD patients.[7] In these studies, plasma CVD risk-related ceramide molecules (Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1)), and their ratios with Cer(d18:1/24:0), emerged as potential risk stratifiers for CAD patients.[4] Ceramides are known to associate with many central processes of atherosclerosis development including lipoprotein uptake, inflammation, and apoptosis (Supplementary material online, Figure S1 ).[8] Ceramide species are produced by six fatty acyl selective ceramide synthases (CerSs; Supplementary material online, Figure S2 ), and it is becoming evident that individual ceramide species have specific physiological functions.[9–12] Thus, monitoring ratios of ceramides species may provide insight into the metabolic regulation of atherosclerotic events. In this study, we establish the suggested role of ceramides and their distinct ratios as risk predictors for CV death in patients with stable CAD and ACS.