Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel

Figures

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  Figure 1. Study design and participant flow Study involves 175 patients with STEMI successfully treated by primary PCI, randomized (1:1) to either clopidogrel or ticagrelor (PLATO trial; NCT00391872). All samples were taken within 12 h of symptoms onset with patients selected from three time-from-symptoms-onset to randomization categories (time points): T0, 0–2 h; T1, 2–4 h; T2, 4–12 h. Discharge plasma was sampled at hospital discharge or 4 days after the baseline sample, whichever came first. ♀/♂, female/male; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcome; STEMI, ST-elevation myocardial infarction.

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  Figure 2. Global metabolomic signature of myocardial infarction (A) First two principal-components analysis of all post-processed samples. Baseline samples are shown in green and discharge samples in orange; treatment with clopidogrel (Clo) in circles and ticagrelor (Tica) in triangles are shown. Proportion of variance explained by each PC is indicated in parentheses on the axis label. (B) Volcano plot showing significant differences between states. p values are obtained from analysis of covariance (ANCOVA) model 1 main effect on state for the full dataset. Fold changes are obtained from the LMM model’s state effect estimate. The top 2 WGCNA modules, represented in blue (mostly amino acids) and in turquoise (mostly fatty acids), map to the decreased and enhanced metabolites at disease states, respectively, whereas the brown module metabolites are non-significant. WGCNA, weighted gene correlation network analysis; BL, baseline; DC, discharge.

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  Figure 3. Omega-3/6 metabolites associated with treatment (A) Volcano plot showing significant differences in metabolite ratios discharge on baseline ratios between treatment groups. p values and fold changes are obtained from the LOGIT model’s treatment effect estimation. (B) Radar plot showing the change in metabolite concentration between baseline and discharge states, with the ticagrelor arm (blue) showing a smaller change compared to clopidogrel arm (red). PUFAs as well as the top 10 increased and decreased metabolites in myocardial infarction are shown. PUFAs, polyunsaturated fatty acids.

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  Figure 4. Clustering and network analyses (A–C) Analyses of metabolites using t-SNE for all patients at baseline (A), clopidogrel patients at discharge (B), and ticagrelor patients at discharge (C) show grouping of metabolites with significant interaction effects (symbols) at baseline (group 4), maintained at discharge in clopidogrel patients but split in ticagrelor patients. (D) RFPimp is used to construct a metabolite network, highlighting metabolites part of the t-SNE group 4 (green) and omega 3/6 metabolites (red). The “sex” variable is physician reported. AHB, 2-hydroxybutyrate; ASM, androsteroid monosulfate 2; t-SNE, t-distributed stochastic neighbor embedding.

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  Figure 5. Omega-3 and omega-6 PUFA pathways Cardiovascular effects of omega-3/6 metabolites noted in sources from the text are shown in this figure. Metabolites found to be significantly modulated by treatment are shown in light blue boxes. The boxes with bold borders are highlighting discriminant metabolites between omega-3 and omega-6 pathways.