Mika Hilvo1, Peter J Meikle2,3, Eva Ringdal Pedersen4, Grethe S Tell5, Indu Dhar6, Hermann Brenner7,8, Ben Schöttker7,8, Mitja Lääperi1, Dimple Kauhanen1, Kaisa M Koistinen1, Antti Jylhä1, Kevin Huynh2, Natalie A Mellett2, Andrew M Tonkin9, David R Sullivan10, John Simes11, Paul Nestel12, Wolfgang Koenig13,14,15, Dietrich Rothenbacher7,15, Ottar Nygård4,6, Reijo Laaksonen1,16,17. 1. Zora Biosciences Oy, Tietotie 2C, 02150 Espoo, Finland. 2. Metabolomics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne VIC 3004, Australia. 3. Department of Diabetes, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, 99 Commercial Road, Melbourne VIC 3004, Australia. 4. Department of Heart Disease, Haukeland University Hospital, Jonas Lies veg 65, 5021 Bergen, Norway. 5. Department of Global Public Health and Primary Care, University of Bergen, Kalfarveien 31, 5020 Bergen, Norway. 6. Department of Clinical Science, University of Bergen, Jonas Lies veg 87, 5021 Bergen, Norway. 7. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany. 8. Network Ageing Research, University of Heidelberg, Bergheimer Straße 20, D-69115 Heidelberg, Germany. 9. School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne VIC 3004, Australia. 10. Department of Chemical Pathology, Royal Prince Alfred Hospital, 50 Missenden Road, Camperdown NSW 2050, Sydney, Australia. 11. The NHMRC Clinical Trials Centre, University of Sydney, 92-94 Parramatta Rd, Camperdown NSW 2050, Sydney, Australia. 12. Heart Centre, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne VIC 3004, Australia. 13. Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, D-80636 Munich, Germany. 14. DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Lazarettstr. 36, D-80636 Munich, Germany. 15. Institute of Epidemiology and Medical Biometry, Helmholtzstr. 22, D-89081 Ulm University, Ulm, Germany. 16. Finnish Cardiovascular Research Center, University of Tampere, Arvo Ylpön katu 34, 33520 Tampere, Finland. 17. Finnish Clinical Biobank Tampere, Tampere University Hospital, Biokatu 12, 33520 Tampere, Finland.
Abstract
AIMS: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. METHODS AND RESULTS: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. CONCLUSION: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.
AIMS: Distinct ceramidelipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. METHODS AND RESULTS:Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. CONCLUSION: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.
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