Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study

Abstract

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

Keywords: atrial fibrillation; biomarker; epidemiology; lipid metabolites; lipids.

Figure 1

Participant mean baseline characteristics and trends across quartiles of sphingolipids among 4206 CHS (Cardiovascular Health Study) participants. *Measured in 1992 to 1993 for all participants. The colored graphics show means or percentages of each characteristic across quartiles of each of the sphingolipids. Unadjusted linear and logistic regression models were used to assess statistically significant (P<0.0022; 0.05/23 characteristics) associations of log‐transformed sphingolipids with each characteristic; statistically significant positive trends are blue, statistically significant negative trends are red, and gray indicates P>0.0022. Cer‐16 indicates ceramide with palmitic acid; Cer‐20, ceramide with arachidic acid; Cer‐22, ceremide with behenic acid; Cer‐24, ceremide with lignoceric acid; CRP, C‐reactive protein; HDL, high‐density lipoprotein; HF, heart failure; LDL, low‐density lipoprotein; LV, left ventricle; MI, myocardial infarction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; Q1, quartile 1 (the mean or percentage of each characteristic among participants with a sphingolipid level in the lowest 25% of the distribution); Q4, quartile 4 (the mean or percentage among participants with a sphingolipid level in the highest 25% of the distribution); SM‐16, sphingomyelin with palmitic acid; SM‐20, sphingomyelin with arachidic acid; SM‐22, sphingomyelin with behenic acid; SM‐24, sphingomyelin with lignoceric acid.

Figure 2

Risk of incident atrial fibrillation per 2‐fold higher sphingolipid level. Hazard ratios and 95% CIs are presented; each line represents a separate model. Model 1 includes adjustment for age, sex, race, and study site; model 2 includes model 1 adjustment terms and additional adjustment for body mass index, systolic blood pressure, treated hypertension, smoking, alcohol use, high‐density lipoprotein, low‐density lipoprotein, PR interval, prevalent diabetes mellitus, heart failure, and history of myocardial infarction; in model 3, in addition to model 2 adjustment terms, ceramide with palmitic acid (Cer‐16) and sphingomyelin with palmitic acid (SM‐16) include adjustment for ceremide with behenic acid (Cer‐22) and sphingomyelin with behenic acid (SM‐22), respectively; ceramide with arachidic acid (Cer‐20), Cer‐22, ceremide with lignoceric acid (Cer‐24) and sphingomyelin with arachidic acid (SM‐20), SM‐22, and sphingomyelin with lignoceric acid (SM‐24) include adjustment for Cer‐16 and SM‐16, respectively.