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

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.

[1]  R. Laaksonen,et al.  Development and validation of a high-throughput LC–MS/MS assay for routine measurement of molecular ceramides , 2016, Analytical and Bioanalytical Chemistry.

[2]  S. Krupenko,et al.  Ceramide Synthase 6 Is a Novel Target of Methotrexate Mediating Its Antiproliferative Effect in a p53-Dependent Manner , 2016, PloS one.

[3]  P. Ridker.  From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. , 2016, Circulation research.

[4]  Jeroen J. Bax,et al.  2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). , 2011, European heart journal.

[5]  H. Nagasaki,et al.  Involvement of de novo ceramide synthesis in pro-inflammatory adipokine secretion and adipocyte-macrophage interaction. , 2014, The Journal of nutritional biochemistry.

[6]  S. Summers,et al.  CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. , 2014, Cell metabolism.

[7]  Matthias Blüher,et al.  Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. , 2014, Cell metabolism.

[8]  A. Futerman,et al.  Ceramide synthases as potential targets for therapeutic intervention in human diseases. , 2014, Biochimica et biophysica acta.

[9]  Evelyn Regar,et al.  In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. , 2014, European heart journal.

[10]  W. März,et al.  Molecular Lipids Identify Cardiovascular Risk and Are Efficiently Lowered by Simvastatin and PCSK9 Deficiency , 2013, The Journal of clinical endocrinology and metabolism.

[11]  E. Boersma,et al.  Cardiovascular risk prediction models in patients with stable coronary artery disease , 2014 .

[12]  P. Libby,et al.  C-Reactive Protein, but not Low-Density Lipoprotein Cholesterol Levels, Associate With Coronary Atheroma Regression and Cardiovascular Events After Maximally Intensive Statin Therapy , 2013, Circulation.

[13]  Jeroen J. Bax,et al.  2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. , 2013, European heart journal.

[14]  Hassan Khan,et al.  Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. , 2013, European heart journal.

[15]  A. Shevchenko,et al.  Plasma Lipid Composition and Risk of Developing Cardiovascular Disease , 2013, PloS one.

[16]  T. Lehtimäki,et al.  Beyond LDL-C lowering: distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency. , 2013, Atherosclerosis.

[17]  B. Gersh,et al.  ESC guidelines on the management of stable coronary artery disease — addenda The Task Force on the management of stable coronary artery disease of the European Society of Cardiology , 2013 .

[18]  Jeroen J. Bax,et al.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation , 2012 .

[19]  I. Haviv,et al.  Plasma Lipidomic Analysis of Stable and Unstable Coronary Artery Disease , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[20]  T. Lauer,et al.  Kardiologische Aspekte der präoperativen Risikostratifizierung , 2011 .

[21]  David A Morrow,et al.  Risk Prediction in Cardiovascular Medicine Cardiovascular Risk Prediction in Patients With Stable and Unstable Coronary Heart Disease , 2010 .

[22]  V. Menuz,et al.  Protection of C. elegans from Anoxia by HYL-2 Ceramide Synthase , 2009, Science.

[23]  Adrian Hernandez,et al.  Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. , 2009, American heart journal.

[24]  J. Bismuth,et al.  Ceramide: a common pathway for atherosclerosis? , 2008, Atherosclerosis.

[25]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[26]  A. Billich,et al.  Sphingolipid metabolizing enzymes as novel therapeutic targets. , 2008, Sub-cellular biochemistry.

[27]  M. Ezekowitz,et al.  High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial. , 2005, European heart journal.

[28]  Á. Avezum,et al.  Predictors of hospital mortality in the global registry of acute coronary events. , 2003, Archives of internal medicine.

[29]  I. Marschner,et al.  Long-term risk stratification for survivors of acute coronary syndromes - Results from the long-term intervention with pravastatin in ischemic disease (LIPID) study , 2001 .

[30]  I. Marschner,et al.  Long-term risk stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study. LIPID Study Investigators. , 2001, Journal of the American College of Cardiology.

[31]  W. März,et al.  Interleukin-6 stimulates LDL receptor gene expression via activation of sterol-responsive and Sp1 binding elements. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[32]  D. Choi,et al.  Involvement of de Novo Ceramide Biosynthesis in Tumor Necrosis Factor-α/Cycloheximide-induced Cerebral Endothelial Cell Death* , 1998, The Journal of Biological Chemistry.

[33]  G. Lozanski,et al.  The sphingomyelin-ceramide pathway participates in cytokine regulation of C-reactive protein and serum amyloid A, but not alpha-fibrinogen. , 1997, The Biochemical journal.

[34]  Y. Hannun.  Functions of Ceramide in Coordinating Cellular Responses to Stress , 1996, Science.