A systems proteolipidomic approach identifies novel circulatory biomarkers for idiopathic dilated cardiomyopathy

Dilated cardiomyopathy (DCM), characterized 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 used a high-resolution mass spectrometry-based integrative omics approach coupled with machine learning. Plasma samples from 360 participants, including patients with DCM and controls, were analyzed to identify specific proteolipidomic alterations. We detected 125 significantly altered lipids (0.8 ≥ FC ≥ 1.2; <i>P</i>_adj < 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 [β2micoglobulin (B2M); 6.85 ± 2.86 μg/mL vs. 4.26 ± 1.25 μg/mL; <i>P</i> < 0.0001] and tetranectin (CLEC3B; 1.99 ± 0.88 μg/mL vs. 2.49 ± 0.90 μg/mL; <i>P</i> = 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 phosphatidic acid (PA) (18:1/20:1), whereas oxidative stress marker 8-OHdG was markedly elevated in DCM plasma. Integrative receiver operating characteristic (ROC) analysis combining top lipid discriminators with B2M and CLEC3B achieved an area under the curve (AUC) of 0.99, surpassing NT-proBNP (0.96). Overall, this study delineates the first comprehensive proteolipidomic signature of DCM and proposes a robust multiparametric biomarker panel with enhanced diagnostic precision.<b>NEW & NOTEWORTHY</b> First study of global proteolipidomic changes in dilated cardiomyopathy (DCM). A machine-learning-guided biomarker pipeline identified 39 lipids and 10 proteins distinguishing DCM. We propose that PE (14:0/22:4), phosphatidic acid (PA) (18:1/20:1), and tetranectin (CLEC3B) may link oxidative stress, apoptosis, and ECM remodeling in DCM. A panel combining the top 8 lipid markers along with β2micoglobulin (B2M) and CLEC3B achieved an area under the curve (AUC) of 0.99, outperforming NT-proBNP and offering superior diagnostic accuracy.