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; Stephan Windecker; Baris Gencer; Eva Ringdal Pedersen; Grethe S Tell; Ottar Nygård; Francois Mach; Juha Sinisalo; Thomas F Lüscher

doi:10.1093/eurheartj/ehw148

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

Eur Heart J. 2016 Jul 1;37(25):1967-76. doi: 10.1093/eurheartj/ehw148. Epub 2016 Apr 28.

Authors

Reijo Laaksonen¹, Kim Ekroos², Marko Sysi-Aho², Mika Hilvo², Terhi Vihervaara², Dimple Kauhanen², Matti Suoniemi², Reini Hurme², Winfried März³, Hubert Scharnagl⁴, Tatjana Stojakovic⁴, Efthymia Vlachopoulou⁵, Marja-Liisa Lokki⁵, Markku S Nieminen⁶, Roland Klingenberg⁷, Christian M Matter⁷, Thorsten Hornemann⁸, Peter Jüni⁹, Nicolas Rodondi¹⁰, Lorenz Räber¹¹, Stephan Windecker¹¹, Baris Gencer¹², Eva Ringdal Pedersen¹³, Grethe S Tell¹⁴, Ottar Nygård¹⁵, Francois Mach¹², Juha Sinisalo⁶, Thomas F Lüscher⁸

Affiliations

¹ Zora Biosciences, Espoo, Finland Medical School, Tampere University, Tampere, Finland Finnish Clinical Biobank Tampere, University Hospital of Tampere, Tampere, Finland reijo.laaksonen@zora.fi.
² Zora Biosciences, Espoo, Finland.
³ Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany synlab Academy, synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany.
⁴ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria.
⁵ Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
⁶ Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Cardiology, University Heart Center, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
⁸ Institute of Clinical Chemistry, University Hospital, Zürich, Switzerland.
⁹ Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, and Department of Medicine, University of Toronto, Toronto, Canada.
¹⁰ Department of General Internal Medicine, University Hospital Bern, Bern, Switzerland Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland.
¹¹ Cardiovascular Center, Department of Cardiology, University Hospital Bern, Bern, Switzerland.
¹² Cardiovascular Center, Department of Cardiology, University Hospital Geneva, Geneva, Switzerland.
¹³ Department of Clinical Science, University of Bergen, Bergen, Norway.
¹⁴ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
¹⁵ Department of Clinical Science, University of Bergen, Bergen, Norway Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

Abstract

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.

Keywords: Acute coronary syndrome; Biomarker; Ceramide; Coronary artery disease; LDL-cholesterol; Prognosis; Risk prediction.

MeSH terms

Acute Coronary Syndrome*
Biomarkers
Ceramides
Cholesterol, LDL
Coronary Artery Disease*
Humans
Prognosis
Prospective Studies
Risk Factors

Substances

Biomarkers
Ceramides
Cholesterol, LDL