Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol.

Reijo Laaksonen,Grethe S Tell,Ottar Nygård,Marko Sysi-Aho,Mika Hilvo,Christian M Matter,Lorenz Räber,Eva Ringdal Pedersen,Dimple Kauhanen,Stephan Windecker,Nicolas Rodondi,Reini Hurme,Thomas F Lüscher,Marja-Liisa Lokki,Matti Suoniemi,Efthymia Vlachopoulou,Terhi Vihervaara,Winfried März,Markku S Nieminen,Thorsten Hornemann,Kim Ekroos,Juha Sinisalo,Hubert Scharnagl,Roland Klingenberg,Peter Jüni,Tatjana Stojaković ,Baran Gencer ,François Mach

doi:10.1093/eurheartj/ehw148

Abstract

AimsThe 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 resultsCorogene 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).ConclusionsDistinct 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.

Highlights

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
We found that the predefined ceramide ratios were significantly higher in 81 patients who died following a CV event within 4.6-year follow-up compared with those who did not die during follow-up (Table 2; Supplementary material online, Table S2)
We have developed a tentative risk score (Supplementary material online, Table S11) based on ceramide concentrations and their ratios to model the clinical use of these risk predictors

Summary

Introduction

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, during the first year.[2] 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. Patients with a favorable prognosis should be identified to avoid drug overuse and associated side effects.[3]

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Results

Conclusion