Abstract 4139864: Effect of P2Y12 Inhibitors on Plasma Metabolomic Changes in Patients with Acute Myocardial Infarction

Introduction/Background: Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Research Question/Hypothesis: The research question focuses on predictive analysis of drug response to P2Y12 inhibitors in patients with AMI prior to the initiation of treatment. Aim of the Study: In the present study, we aimed to investigate the metabolic profiles of plasma samples from AMI patients to identify potential disease biomarkers and to study patients after AMI treated with ticagrelor or clopidogrel. Methods: Twenty-two (22) patients with the first AMI were randomized to ticagrelor or clopidogrel. Plasma samples were obtained at three time points (24 hours, 72 hours, and 6 months) from AMI patients. Metabolic profiles of the plasma of 22 AMI patients and 11 controls (longitudinal sample size (N) = 77) were obtained, and over 1000 plasma metabolites were assayed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The Aligned Rank Transform (ARTool) R package was used as a nonparametric equivalent to the multi-factorial repeated measures analysis of variance (ANOVA) and post hoc analysis. Results: Trigonelline from the alkaloid group of metabolites was identified as a uniquely affected metabolite in paired comparisons for AMI patients. After 6 months, trigonelline levels were higher in patients on ticagrelor compared to those on ticagrelor at 72 hours after the switch and those on clopidogrel at 24 hours (p.adjusted (p.adj) = 0.017, p.adj = 0.038, respectively). Other affected groups of metabolites included triacylglycerols (TAGs) and triglycerides (TGs). Up and down-regulated metabolites are presented in Figure 1. Glycolithocholic acid sulfate (GLCAS) and Citrulline were upregulated, while TG was downregulated in clopidogrel group compared to ticagrelor group. phospholipids were found to be significantly lower in the AMI patients compared to control group (p<0.001, see Figure 2). Conclusion: Our study showed that increasing levels of the trigonelline metabolite are associated with long-term response to ticagrelor treatment. Trigonelline is a product of niacin metabolism and a common plant alkaloid that has been shown to reduce platelet aggregation. It acts by affecting β-cell regeneration, insulin secretion, activities of enzymes related to glucose metabolism, reactive oxygen species (ROS), axonal extension, and neuron excitability.