Sphingolipids as Mediators of the Markers of Kidney Function/Heart Failure Association: The Multi-Ethnic Study of Atherosclerosis

BACKGROUND: Heart failure is a common complication of CKD. Sphingolipids, including ceramides and sphingomyelins, are lipid molecules with regulatory and signaling properties. Sphingolipids associated with kidney function and incident heart failure. We previously demonstrated that sphingolipids partially mediate the association between kidney function and incident heart failure. We sought to confirm this finding in the Multi-Ethnic Study of Atherosclerosis. METHODS: All sphingolipids were measured at baseline using tandem-mass spectrometry. Baseline kidney function was assessed using albuminuria and estimated glomerular filtration rate (eGFR). Associations of albuminuria and eGFR with heart failure were tested by Cox and Weibull regressions. We tested the mediation effect of sphingolipids on the associations of eGFR and albuminuria with heart failure via quasi-Bayesian Monte Carlo method based on normal approximation with 2,000 simulations. Analyses tested Bonferroni-corrected p-values 0.00625 (0.05/8 sphingolipids). RESULTS: Among 3,959 participants, the mean (SD) eGFR was 95 (17) mL/min/1.73 m2, and median (Q1, Q3) albuminuria was 5.10 (3.20, 10.2) mg/g creatinine. We observed 438 incident heart failure events over a median (Q1, Q3) follow-up of 18.9 (15.0, 19.6) years. Greater ceramide and sphingomyelin 16:0 and lesser sphingomyelin 20:0 were associated with higher heart failure risk. Sphingomyelin 16:0 was associated with partial 9%, 95% CI 3%, 30%) mediation of the association between eGFR and heart failure, and 4% (1%, 9%) mediation of the association between albuminuria and heart failure. Sphingomyelin 20:0 partially mediated the eGFR/heart failure association (6%, 95% CI 1%, 21% of association mediated). CONCLUSIONS: Plasma sphingomyelins were associated with partial mediation of the associations of eGFR and albuminuria with incident heart failure.