The role of sphingolipids in heart failure

Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction. In animal models of obesity, accumulation of toxic sphingolipid metabolites in the heart has been described as cardiac lipotoxicity. In humans, HF is classified into two groups based on ejection fraction (EF): HF with reduced EF of less than 40% (HFrEF) and HF with preserved EF of greater than 50% (HFpEF). Despite shared risk factors and comorbidities, the structural and cellular differences between HFrEF and HFpEF distinguish them as separate conditions. Ceramides (Cer), a type of sphingolipid, have gained significant attention for their involvement in the development and prognosis of atherosclerotic disease and myocardial infarction, while sphingosine-1-phosphate, a downstream product of Cer, has shown cardioprotective properties. The aim of this review is to describe the role of sphingolipids in HF with reduced and preserved EF. By understanding the role of sphingolipids through animal and human studies, this review aims to pave the way for developing strategies that target abnormal signalling pathways in the failing heart, ultimately bridging the gap between scientific research and clinical applications.