A Systems Proteo-Lipidomic Approach Identifies Novel Circulatory Biomarkers for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM), characterised by left ventricular dilation and systolic dysfunction, remains a major cause of heart failure, necessitating improved diagnostic strategies. Conventional imaging techniques such as echocardiography and MRI, along with classical cardiovascular markers like NT-proBNP and cTnT, demonstrate limited sensitivity for DCM-specific phenotypes. Given the critical role of lipids and proteins in cardiac physiology, their alteration may provide disease-specific diagnostic insights. To address the scarcity of comprehensive lipidomic studies and validated protein biomarkers in DCM, we employed a high-resolution mass spectrometry–based integrative omics approach coupled with machine learning. Plasma samples from 360 participants, including DCM patients and controls, were analysed to identify specific proteo-lipidomic alterations. We detected 125 significantly altered lipids (0.8 ≥ FC ≥ 1.2; padj < 0.05) and 10 proteins, of which 39 lipids and 10 proteins were identified as primary discriminators using a Boruta-based ML approach. ELISA validation confirmed β2-microglobulin (B2M; 6.85 ± 2.86 μg/ml vs. 4.26 ± 1.25 μg/ml; p < 0.0001) and tetranectin (CLEC3B; 1.99 ± 0.88 μg/ml vs. 2.49 ± 0.90 μg/ml; p = 0.0006) as significant protein biomarkers. Single-cell transcriptomic data from DCM myocardium supported these trends, showing cell-type—specific alterations in B2M and CLEC3B expression. CLEC3B was positively correlated with PA(18:1/20:1), while oxidative stress marker 8-OHdG was markedly elevated in DCM plasma. Integrative ROC analysis combining top lipid discriminators with B2M and CLEC3B achieved an AUC of 0.99, surpassing NT-proBNP (0.96). Overall, this study delineates the first comprehensive proteo-lipidomic signature of DCM and proposes a robust multiparametric biomarker panel with enhanced diagnostic precision.