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

      1 , 2 , 3 , * , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 4 , 5 , 6 , 6 , 7 , 7 , 7 , 8 , 9 , 9 , 10 , 11 , 12 , 13 , 14 , 14 , 15 , 16 , 17 , 16 , 18 , 15 , 7 , 8 , 10

      European Heart Journal

      Oxford University Press

      Ceramide, Acute coronary syndrome, Coronary artery disease, Biomarker, LDL-cholesterol, Risk prediction, Prognosis

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          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.

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          Most cited references 16

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          Predictors of hospital mortality in the global registry of acute coronary events.

          Management of acute coronary syndromes (ACS) should be guided by an estimate of patient risk. To develop a simple model to assess the risk for in-hospital mortality for the entire spectrum of ACS treated in general clinical practice. A multivariable logistic regression model was developed using 11 389 patients (including 509 in-hospital deaths) with ACS with and without ST-segment elevation enrolled in the Global Registry of Acute Coronary Events (GRACE) from April 1, 1999, through March 31, 2001. Validation data sets included a subsequent cohort of 3972 patients enrolled in GRACE and 12 142 in the Global Use of Strategies to Open Occluded Coronary Arteries IIb (GUSTO-IIb) trial. The following 8 independent risk factors accounted for 89.9% of the prognostic information: age (odds ratio [OR], 1.7 per 10 years), Killip class (OR, 2.0 per class), systolic blood pressure (OR, 1.4 per 20-mm Hg decrease), ST-segment deviation (OR, 2.4), cardiac arrest during presentation (OR, 4.3), serum creatinine level (OR, 1.2 per 1-mg/dL [88.4- micro mol/L] increase), positive initial cardiac enzyme findings (OR, 1.6), and heart rate (OR, 1.3 per 30-beat/min increase). The discrimination ability of the simplified model was excellent with c statistics of 0.83 in the derived database, 0.84 in the confirmation GRACE data set, and 0.79 in the GUSTO-IIb database. Across the entire spectrum of ACS and in general clinical practice, this model provides excellent ability to assess the risk for death and can be used as a simple nomogram to estimate risk in individual patients.
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            Functions of ceramide in coordinating cellular responses to stress.

             Yusuf Hannun (1996)
            Sphingolipid metabolites participate in key events of signal transduction and cell regulation. In the sphingomyelin cycle, a number of extracellular agents and insults (such as tumor necrosis factor, Fas ligands, and chemotherapeutic agents) cause the activation of sphingomyelinases, which act on membrane sphingomyelin and release ceramide. Multiple experimental approaches suggest an important role for ceramide in regulating such diverse responses as cell cycle arrest, apoptosis, and cell senescence. In vitro, ceramide activates a serine-threonine protein phosphatase, and in cells it regulates protein phosphorylation as well as multiple downstream targets [such as interleukin converting enzyme (ICE)-like proteases, stress-activated protein kinases, and the retinoblastoma gene product] that mediate its distinct cellular effects. This spectrum of inducers of ceramide accumulation and the nature of ceramide-mediated responses suggest that ceramide is a key component of intracellular stress response pathways.
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              Ceramide synthases as potential targets for therapeutic intervention in human diseases.

              Ceramide is located at a key hub in the sphingolipid metabolic pathway and also acts as an important cellular signaling molecule. Ceramide contains one acyl chain which is attached to a sphingoid long chain base via an amide bond, with the acyl chain varying in length and degree of saturation. The identification of a family of six mammalian ceramide synthases (CerS) that synthesize ceramide with distinct acyl chains, has led to significant advances in our understanding of ceramide biology, including further delineation of the role of ceramide in various pathophysiologies in both mice and humans. Since ceramides, and the complex sphingolipids generated from ceramide, are implicated in disease, the CerS might potentially be novel targets for therapeutic intervention in the diseases in which the ceramide acyl chain length is altered. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                ehj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                01 July 2016
                28 April 2016
                28 April 2016
                : 37
                : 25 , Focus Issue on Lipids
                : 1967-1976
                Affiliations
                [1 ]Zora Biosciences , Espoo, Finland
                [2 ]Medical School, Tampere University , Tampere, Finland
                [3 ]Finnish Clinical Biobank Tampere, University Hospital of Tampere , Tampere, Finland
                [4 ]Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg , Heidelberg, Germany
                [5 ]synlab Academy, synlab Holding Deutschland GmbH , Mannheim and Augsburg, Germany
                [6 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz , Graz, Austria
                [7 ]Transplantation Laboratory, Haartman Institute, University of Helsinki , Helsinki, Finland
                [8 ]Heart and Lung Center, Helsinki University Hospital , Helsinki, Finland
                [9 ]Department of Cardiology, University Heart Center, University Hospital Zürich and University of Zürich , Zürich, Switzerland
                [10 ]Institute of Clinical Chemistry, University Hospital , Zürich, Switzerland
                [11 ]Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, and Department of Medicine, University of Toronto , Toronto, Canada
                [12 ]Department of General Internal Medicine, University Hospital Bern , Bern, Switzerland
                [13 ]Department of Ambulatory Care and Community Medicine, University of Lausanne , Lausanne, Switzerland
                [14 ]Cardiovascular Center, Department of Cardiology, University Hospital Bern , Bern, Switzerland
                [15 ]Cardiovascular Center, Department of Cardiology, University Hospital Geneva , Geneva, Switzerland
                [16 ]Department of Clinical Science, University of Bergen , Bergen, Norway
                [17 ]Department of Global Public Health and Primary Care, University of Bergen , Bergen, Norway
                [18 ]Department of Heart Disease, Haukeland University Hospital , Bergen, Norway
                Author notes
                [* ]Corresponding author. Zora Biosciences Oy, Biologinkuja 1, 02150 Espoo, Finland. Tel: +358 40 724 077, Email: reijo.laaksonen@ 123456zora.fi
                [†]

                Equal contribution.

                Article
                ehw148
                10.1093/eurheartj/ehw148
                4929378
                27125947
                © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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