Links between ceramides and cardiac function

Abstract

Purpose of review: Total ceramide levels in cardiac tissue relate to cardiac dysfunction in animal models. However, emerging evidence suggests that the fatty acyl chain length of ceramides also impacts their relationship to cardiac function. This review explores evidence regarding the relationship between ceramides and left ventricular dysfunction and heart failure. It further explores possible mechanisms underlying these relationships.

Recent findings: In large, community-based cohorts, a higher ratio of specific plasma ceramides, C16 : 0/C24 : 0, related to worse left ventricular dysfunction. Increased left ventricular mass correlated with plasma C16 : 0/C24 : 0, but this relationship became nonsignificant after adjustment for multiple comparisons. Decreased left atrial function and increased left atrial size also related to C16 : 0/C24 : 0. Furthermore, increased incident heart failure, overall cardiovascular disease (CVD) mortality and all-cause mortality were associated with higher C16 : 0/C24 : 0 (or lower C24 : 0/C16 : 0). Finally, a number of possible biological mechanisms are outlined supporting the link between C16 : 0/C24 : 0 ceramides, ceramide signalling and CVD.

Summary: High cardiac levels of total ceramides are noted in heart failure. In the plasma, C16 : 0/C24 : 0 ceramides may be a valuable biomarker of preclinical left ventricular dysfunction, remodelling, heart failure and mortality. Continued exploration of the mechanisms underlying these profound relationships may help develop specific lipid modulators to combat cardiac dysfunction and heart failure.

Figure 1.

Risk of incident coronary heart disease (CHD), heart failure (HF), and all-cause mortality by the plasma C24:0/C16:0 ceramide ratio. Hazard ratios (HRs) for CHD, HF, and all-cause mortality are reported with 95% confidence intervals (CIs) for each 3-unit increase in the plasma 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. Reproduced with permission from reference #.

Figure 2.

Representation of ceramide synthesis and degradation. The salvage pathway, De novo pathway, and sphingomyelinase synthesis pathway are show along with the degradation pathway. The protein abbreviations and full names are listed in the bottom right corner.

Figure 3.

Diagram of ceramide signaling in the mitochondria in cardiomyocytes. (A) shows the release of cyt c through ceramide channels in the mitochondrial outer membrane leading to an increase in caspase 3 and apoptosis. (B) C24:0 ceramide inducing mitochondrial fragmentation and leading to a decrease in inner mitochondrial membrane potential and an inhibition of mitochondrial Ca²⁺ buffer capacity. (C) Increase in cytoplasmic Ca²⁺ from C24:0 mediated Ca²⁺ release from the ER and loss of Ca²⁺ buffer capacity in the mitochondria. The Ca²⁺ flux induces apoptosis through calpains.

Figure 4.

Diagram of ceramides’ interaction with ion channels. (A) C16:0 ceramide closing the Kv1.3 channel and contributing to inflammation and atherosclerosis. (B) C2 ceramide activating VRAC and contributing to cardiac hypotrophy and Ischemia-reperfusion injury. (C) Shows two different mechanisms of C2 and C6 ceramides effects on hERG. (C.1) C2 and C6 ceramides deactivate hERG, closing the channel and (C.2) cause ubiquitin mediated degradation in the lysosome. The decrease in hERG activity impaired action potential repolarization, leading to QT prolongation and cardiac arrhythmia.