Abstract 18921: Lipotoxic Induction of Myocardial and Circulating Very Long-chain Ceramides in Patients With Advanced Heart Failure Improves With Mechanical Unloading Through Ventricular Assist Devices
Introduction: Our recent work has demonstrated accumulation of lipotoxic ceramides in animal models of heart failure (HF). Ceramide accumulation and abnormal sphingolipid metabolism might constitute a key link between altered cellular metabolism, apoptosis and cardiac dysfunction.
Hypothesis: We hypothesized that changes in circulating and myocardial ceramide species contribute to myocardial dysfunction in advanced HF patients (pts) and improve after hemodynamic correction through LVAD.
Methods: Serum and myocardium were collected from 34 pts with HF before, 28 pts after LVAD (15 paired pts) and 22 controls (con). Ceramides were measured by LC/MS. Protein expression was detected by Western blot. To study ceramide metabolism in vitro, AC16 human cardiomyocyte-like cells overexpressing serine palmitoyltransferase-1 (SPT1), the rate limiting enzyme of de novo ceramide synthesis, were cultured.
Results: In human HF samples, total ceramides (13.1±1.1 vs. 8.2±1.2 nmol/g in con, p<0.05) and subspecies C16:1, C16 and C24:1 were higher (C16:1: 16.0±22.1 vs. 31.1±7.2 pmol/g in con, p<0.01; C16: 2.0±0.3 vs. 0.9±0.2 nmol/g in con, p<0.05; C24:1: 4.7±0.5 vs. 2.4±0.4 pmol/g in con, p<0.01). Total serum ceramide was not altered but showed increased C16:1: 17.7±1.6 vs. 11.2±1.1 nM in con, C16: 259.1±11.6 vs. 201.2±8.5 nM in con and C18: 129.6±9.8 vs. 97.1±8.5 nM in con (all p<0.05). Mechanical unloading decreased myocardial total ceramides (9.9±0.9 vs. 13.1±1.1 nmol/g pre-LVAD, p<0.05) as well as individual ceramides C16:1, C16, C20:1, C20, C22:1, C22 and C24:1 (all p<0.05 vs. pre-LVAD). Total serum ceramide levels normalized after LVAD (4.4±0.3 vs. 3.5±0.1 uM pre-LVAD, p<0.05). LVAD reduced protein expression of SPT1 by 39% which was 57% higher in failing myocardium compared to con. In AC16 cells overexpressing SPT1, total ceramides increased by 97% (p<0.05 vs. con).
Conclusions: Myocardial total ceramide content and subspecies accumulate in advanced HF pts consistent with myocardial lipotoxicity which is partially corrected by mechanical unloading through LVAD placement. Our findings suggest a crucial activation of de novo ceramide synthesis contributing to myocardial lipotoxicity and abnormal metabolism in advanced HF.
Author Disclosures: R. Ji: None. L.Y. Deng: None. X. Liao: None. X. Zhang: None. H. Jiang: None. R. Givens: None. E. Castillero: None. P. Kennel: None. I. George: None. P. Schulze: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.