Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort

Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiov...

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Published in:	Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 12; pp. 2424 - 2430
Main Authors:	Havulinna, Aki S, Sysi-Aho, Marko, Hilvo, Mika, Kauhanen, Dimple, Hurme, Reini, Ekroos, Kim, Salomaa, Veikko, Laaksonen, Reijo
Format:	Journal Article
Language:	English
Published:	United States 01.12.2016
Subjects:	Adult Aged Biomarkers - blood Cardiovascular Diseases - blood Cardiovascular Diseases - diagnosis Cardiovascular Diseases - epidemiology Cardiovascular Diseases - mortality Ceramides - blood Chromatography, Liquid Comorbidity Female Finland - epidemiology Humans Incidence Kaplan-Meier Estimate Life Style Male Middle Aged Predictive Value of Tests Prevalence Prognosis Proportional Hazards Models Recurrence Risk Assessment Risk Factors Tandem Mass Spectrometry Time Factors Up-Regulation Finland lipids risk factors cardiovascular diseases metabolomics ceramides lipidomics
ISSN:	1524-4636
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Abstract	Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals. FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography-tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9×10 ) for Cer(d18:1/18:0). Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk.
AbstractList	OBJECTIVECeramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals.APPROACH AND RESULTSFINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography-tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9×10-5) for Cer(d18:1/18:0).CONCLUSIONSDistinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk. Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals. FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography-tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9×10 ) for Cer(d18:1/18:0). Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk.
Author	Hilvo, Mika Havulinna, Aki S Sysi-Aho, Marko Kauhanen, Dimple Hurme, Reini Ekroos, Kim Salomaa, Veikko Laaksonen, Reijo
Author_xml	– sequence: 1 givenname: Aki S surname: Havulinna fullname: Havulinna, Aki S organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 2 givenname: Marko surname: Sysi-Aho fullname: Sysi-Aho, Marko organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 3 givenname: Mika surname: Hilvo fullname: Hilvo, Mika organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 4 givenname: Dimple surname: Kauhanen fullname: Kauhanen, Dimple organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 5 givenname: Reini surname: Hurme fullname: Hurme, Reini organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 6 givenname: Kim surname: Ekroos fullname: Ekroos, Kim organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 7 givenname: Veikko surname: Salomaa fullname: Salomaa, Veikko organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.) – sequence: 8 givenname: Reijo surname: Laaksonen fullname: Laaksonen, Reijo email: reijo.laaksonen@zora.fi organization: From the Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.); Zora Biosciences Oy, Espoo, Finland (M.S.-A., M.H., D.K., R.H., K.E., R.L.); Medical School, University of Tampere, Finland (R.L.); and Finnish Clinical Biobank, University Hospital of Tampere, Finland (R.L.). reijo.laaksonen@zora.fi
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Keywords	lipids risk factors cardiovascular diseases metabolomics ceramides lipidomics
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PublicationTitle	Arteriosclerosis, thrombosis, and vascular biology
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SubjectTerms	Adult Aged Biomarkers - blood Cardiovascular Diseases - blood Cardiovascular Diseases - diagnosis Cardiovascular Diseases - epidemiology Cardiovascular Diseases - mortality Ceramides - blood Chromatography, Liquid Comorbidity Female Finland - epidemiology Humans Incidence Kaplan-Meier Estimate Life Style Male Middle Aged Predictive Value of Tests Prevalence Prognosis Proportional Hazards Models Recurrence Risk Assessment Risk Factors Tandem Mass Spectrometry Time Factors Up-Regulation
Title	Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort
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