Comprehensive Plasma Oxylipin Profiling Reveals a Pro-Inflammatory Eicosanoid Signature and Diagnostic Biomarker...

BACKGROUND Dilated cardiomyopathy (DCM) is characterized by chronic myocardial inflammation and remodeling. Polyunsaturated fatty acid-derived oxylipins are critical mediators of cardiac inflammation; their plasma profiles in DCM and diagnostic potential remain undefined. We aimed to comprehensively quantify plasma oxylipins in patients with DCM, identify dysregulated lipid pathways, and develop a noninvasive biomarker panel for disease classification. MATERIAL AND METHODS Seventy-three oxylipins were quantified by targeted ultra-high-performance liquid chromatography-tandem mass spectrometry in plasma samples from 30 patients with DCM and 30 age/sex-matched healthy controls. Differential metabolites were identified using Wilcoxon rank-sum tests, significance analysis of microarrays (SAM), and empirical Bayes analysis of microarrays (EBAM). Intersecting features defined a high-confidence signature. Ingenuity Pathway Analysis (IPA) detected enriched lipid mediator pathways. Diagnostic performance was evaluated with a support vector machine (SVM) model using hold-out validation. RESULTS Sixteen oxylipins significantly differed according to Wilcoxon testing. Overlap with SAM and EBAM identified 14 core metabolites dominated by lipoxygenase-derived hydroxyeicosatetraenoic acids, cyclooxygenase-derived prostaglandin E2, and cytochrome P450-derived hydroxyeicosapentaenoic acids, with concomitant suppression of pro-resolving mediators. IPA revealed activation of eicosanoid signaling, triggering receptor expressed on myeloid cells 1 signaling, and prostanoid biosynthesis. A 6-marker SVM panel (15-oxo-eicosatetraenoic acid, 9-hydroxyeicosatetraenoic acid, 6R-lipoxin A4, prostaglandin E2, 16-hydroxyeicosatetraenoic acid, and 18-hydroxyeicosapentaenoic acid) achieved an area under the curve of 0.876 (sensitivity 74.2%, specificity 75.9%). CONCLUSIONS DCM is associated with a dominant pro-inflammatory oxylipin milieu and impaired resolution signaling. The 6-oxylipin panel provides a noninvasive diagnostic tool and suggests lipid mediator pathways represent therapeutic targets in heart failure.