Circulating ceramides and sphingomyelins: key biomarkers and targets in cardiovascular prevention

Circulating sphingolipids, composed of a sphingoid backbone, a fatty acid chain, and a polar head group, exert important physiological effects and are dysregulated in various metabolic disorders. Ceramides and sphingomyelins (SM) may contribute to elevated cardiovascular risk via pathways that are independent of traditional lipid metabolism, playing an important role in identifying residual risk. However, the impacts of specific types of ceramides and sphingomyelins on cardiovascular outcomes remain uncertain. In this review, we (i) summarize the latest advances in prospective evidence linking circulating ceramides and sphingomyelins to cardiovascular diseases (CVD), (ii) discuss improvements in predicting adverse cardiovascular outcomes using comprehensive risk scores based on ceramides, and (iii) further illustrate potential modifiable factors influencing ceramides and sphingomyelins levels, such as diet, physical activity, and air pollutants. In conclusion, circulating ceramides and sphingomyelins are valuable cardiovascular risk biomarkers, serving as key factors in both primary and secondary prevention by identifying the additional risk of CVD independent of conventional lipid biomarkers, with distinct roles among different types of ceramides and sphingomyelins. Further studies are urgently needed to elucidate the causal relationships between specific types of circulating ceramides or sphingomyelins and subtypes of CVD and their underlying biological mechanisms. To advance the practical application of ceramides and other sphingolipids in the prevention and treatment of CVD, large-scale studies are required to determine the extent to which modifiable factors reduce cardiovascular risk by regulating ceramide and sphingomyelin levels, and continued efforts should be focused on targeted interventions and clinical translation in sphingolipid metabolism.