Sphingomyelin as a key negative mediator in atrial fibrillation via lipid profiling analysis and functional identification.

AIMS: Atrial fibrillation (AF) has emerged as one of the most prevalent cardiac arrhythmias globally, with its incidence continuously rising, thereby elevating it to a major public health concern. The heart is known for its high lipid content, and disorders or abnormalities in lipid metabolism are frequently associated with cardiovascular diseases. This study aims to investigate the regulatory roles of lipids in AF. METHODS AND RESULTS: Using tree-based ensemble learning-assisted lipidomics, sphingomyelin was identified as a key differential metabolite and found to be significantly reduced in AF patients. Exogenous supplementation of sphingomyelin significantly attenuated Ach-CaCl2- and Ang II-induced AF, fibrosis, and inflammation in mice. Furthermore, decreased sphingomyelin levels were attributed to increased activity of sphingomyelin phosphodiesterases (SMPDs) under AF conditions. Mechanistically, RNA-Seq analysis demonstrated that sphingomyelin inhibits AF-induced activation of the Rap1 signaling pathway, a finding corroborated by overexpression and knockdown of RAP1 in vivo. CONCLUSION: Together, these findings highlight the therapeutic potential of sphingomyelin and SMPD inhibitors in mitigating AF through inhibition of the Rap1 signaling pathway, thereby establishing the targeting of sphingomyelin metabolism as a viable and novel treatment strategy for AF.