S1P as a novel target to address adverse outcomes following acute myocardial infarction
C Balbi, Y Wang, E Pavlidou, M Allemann, A Seeberger, S Kraler, G Camici, T Luscher, H J BeerAbstract
Introduction
Sphingosine-1-phosphate (S1P) is a bioactive lipid mainly released by platelets during activation, particularly in the setting of acute myocardial infarction (AMI). Data on the role of S1P in AMI pathophysiology remains limited.
Purpose
This project aims to elucidate the mechanistic role of S1P in cardiac remodelling following AMI, and to evaluate its potential as a predictive biomarker of cardiovascular risk.
Materials&Methods
Quantitative lipidomics on 440 human plasma samples obtained from AMI patients was performed. By harnessing human iPS-derived cardiomyocytes, human cardiac fibroblasts and 3D cardiac microtissue models, comprehensive in vitro analyses of the role of S1P in cardiac cells was performed.
Results
Lipidomic analysis of AMI human patient samples revealed significantly elevated circulating S1P levels in individuals who later developed secondary major adverse cardiovascular events (MACE) (p < 0.05), supporting its potential pathogenic role in post-MI outcomes. In vitro, S1P promoted fibroblast activation, evidenced by an increase in αSMA+ cells and enhanced Collagen-1 secretion (p < 0.05 and p < 0.001, respectively), findings that were preliminarily confirmed in a 3D culture model. Additionally, S1P induced cardiomyocyte hypertrophy, as demonstrated by upregulation of NPPB and NPPA gene expression (p < 0.05 and p < 0.001, respectively) and increased cell area (p < 0.001), while concurrently reducing cell viability (p < 0.001). Finally, clinical data analysis indicated that elevated S1P levels were associated with increased susceptibility to MACE (p<0.001) and correlated with myocardial damage, as measured by CK-MB (p<0.01).
Conclusion
By integrating molecular insights with clinical outcome data, we established S1P as a mechanistic driver and potential biomarker of post-MI remodelling and MACE. These findings may support the development of novel diagnostic tools and therapeutic approaches aimed at mitigating post-infarction damage and improving both short- and long-term outcomes.Figure 1