Abstract 15509: Circulating Ceramides Predict Fatal and All Incident Major Adverse Cardiovascular Events: A Prospective Analysis of the FINRISK 2002 Cohort

Abstract

Introduction: Ceramides are molecular lipids assumed to play a role in apoptosis, inflammation, obesity and insulin resistance. A recent study reported that certain ceramides were associated with fatal outcome among patients with CHD. Hypothesis: We hypothesized that ceramides are associated with incident cardiovascular (CVD) outcomes among apparently healthy individuals over and above the traditional risk factors. Methods: FINRISK 2002 is a population-based risk factor survey, which recruited 8,798 men and women aged 25-74 years. The participation rate was 65.5%. The cohort was followed up through 31 Dec, 2011, for incident CVD events and through 31 Dec, 2012, for deaths. Our primary outcome was major adverse cardiovascular events (MACE, n= 471). Secondary analyses were carried out for fatal MACE (n=137). Four circulating ceramides (Cer d18:1/16:0, Cer d18:1/18:0, Cer d18:1/24:0, and Cer d18:1/24:1) were determined from frozen samples using mass spectrometry. We used Cox proportional hazard models with age as the time scale to determine associations of the ceramides with incident outcomes. All models were stratified by sex and the full models were adjusted for geographic region, total and HDL-cholesterol, systolic blood pressure, blood pressure medication, BMI, smoking and diabetes. The predictive ability of the ceramides was assessed by estimating the 10-year absolute risk of MACE and comparing the full models with and without ceramides. The predictions were done using 10-fold cross-validated Weibull proportional hazard models. Results: When considered one by one, three out of the four ceramides were significantly associated with the risk of incident MACE in the fully adjusted Cox models. Ceramide score, formed as a linear combination of the four ceramides had a hazard ratio (HR) of 1.75 (p=0.005) in the full model. C-statistics did not change significantly but the net reclassification improvement among persons with intermediate risk was significant 6.2% (2.6 - 9.7%). The association of the ceramide score with fatal MACE was even stronger than with all MACE: HR=2.31 (p=0.02). Conclusions: These results show the potential of lipidomics profiling in producing new insights in the pathogenesis of CVD and suggesting new therapeutic targets.