Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Abstract

Background: Recent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community-based samples.

Methods and results: We developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very-long-chain/long-chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow-up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow-up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta-analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inversely associated with incident CHD (hazard ratio per average SD increment, 0.79; 95% confidence interval, 0.71-0.89; P<0.0001) and inversely associated with incident HF (hazard ratio, 0.78; 95% confidence interval, 0.61-1.00; P=0.046). Moreover, the C24:0/C16:0 and C22:0/C16:0 ceramide ratios were inversely associated with all-cause mortality (C24:0/C16:0: hazard ratio, 0.60; 95% confidence interval, 0.56-0.65; P<0.0001; C22:0/C16:0: hazard ratio, 0.65; 95% confidence interval, 0.60-0.70; P<0.0001).

Conclusions: The ratio of C24:0/C16:0 ceramides in blood may be a valuable new biomarker of CHD risk, HF risk, and all-cause mortality in the community.

Keywords: cardiovascular disease risk factors; ceramides; mortality.

Figure 1

Distributions of plasma ceramide ratios in FHS (Framingham Heart Study) and SHIP (Study of Health in Pomerania). Plots display distribution of values for C24:0/C16:0 (A and C) and C22:0/C16:0 (B and D) ceramide ratios in female and male FHS participants at examination 8 (A and B) and in SHIP participants at SHIP‐1 examination (C and D).

Figure 2

Cumulative incidence of coronary heart disease (CHD), heart failure (HF), and all‐cause mortality in FHS (Framingham Heart Study) by tertiles of plasma C24:0/C16:0 ceramide ratio. Cumulative incidence of CHD (A), HF (B), and all‐cause mortality (C) are reported for tertiles of C24:0/C16:0 ceramide ratio. Tertile 1 includes participants with ceramide levels at the 33rd percentile or lower (2.8–12.3 μg/mL); tertile 2 includes participants with ceramide levels between >33rd and <66th percentile (12.3–15.1 μg/mL); tertile 3 includes participants with ceramide levels ≥66th percentile (15.1–29.2 μg/mL).

Figure 3

Risk of coronary heart disease (CHD), heart failure (HF), and all‐cause mortality by C24:0/C16:0 ceramide ratio. Hazard ratios (HRs) for CHD, HF, and all‐cause mortality are reported with 95% confidence intervals (CIs) for a 3‐unit increase in the C24:0/C16:0 ceramide ratio (average of SDs between FHS [Framingham Heart Study] and SHIP [Study of Health in Pomerania]), adjusting for all other variables in the model. Data are shown from analysis of subjects in FHS, SHIP, and the combined meta‐analysis (META). I²=0 for CHD and for all‐cause mortality; I²=0.81 for HF.

Figure 4

Risk of cardiovascular disease (CVD) mortality and non‐CVD mortality by ceramide ratios. Hazard ratios (HRs) for CVD mortality and non‐CVD mortality are reported with 95% confidence intervals (CIs) for a 3‐unit increase in C24:0/C16:0 ceramide ratio and for a 0.7‐unit increase in C22:0/C16:0 ceramide ratio (for each ratio, average of SDs between FHS [Framingham Heart Study] and SHIP [Study of Health in Pomerania]), adjusting for all other variables in the model. Data are shown from analysis of subjects in FHS, SHIP, and the combined meta‐analysis (META). I²=0 for CVD mortality and for non‐CVD mortality.