Circulating miRNA-Protein Signatures Predict Outcomes in Pediatric Dilated Cardiomyopathy
BackgroundPediatric dilated cardiomyopathy (DCM) is a rare, progressive heart disease with variable outcomes that range from recovery to heart transplantation. To date, there are no prognostic biomarkers for children with DCM. Identifying circulating biomarkers that are associated with clinical outcomes is critical for personalized management. MethodsmiRNAs were identified by RNA-seq, whereas proteins were identified by SomaScan(R). Machine learning methodologies were used to explore the predictive ability of circulating factors identified from serum samples collected at the time of presentation with acute heart failure. ResultsThirty patients experienced poor outcomes (cardiac transplantation, mechanical circulatory support, or death) and 19 patients recovered left ventricular function. Distinct miRNA and protein signatures differentiated outcomes groups. Top candidate proteins (COL2A1, CXCL12, and ADGRF5) and miRNAs (miR-874-3p, miR-335-3p, miR-323a-3p) demonstrated strong discriminatory performance within the study cohort (recovered vs poor outcomes; Area Under the Curve of 0.92). Ingenuity Pathway Analysis implicates cardiac remodeling, fibrosis, and inflammatory signaling as central pathways differentiating patient outcomes. ConclusionsCirculating miRNA and protein signatures at presentation identify a circulating molecular signature associated with divergent clinical trajectories in pediatric DCM. These findings support the potential utility of multi-omic biomarkers for early risk stratification and provide insight into mechanisms underlying divergent outcomes. CLINICAL PERSPECTIVEWhat Is New? O_LICirculating miRNA and protein profiles measured at presentation distinguish children with pediatric DCM who recover from those who progress to advanced heart failure. C_LIO_LIA combined multi-omic biomarker demonstrated strong discriminatory performance in this cohort (AUC 0.92). C_LIO_LIPathway analysis implicates extracellular matrix remodeling, fibrosis, and inflammatory signaling in children with adverse clinical trajectories. C_LI What Are the Clinical Implications? O_LISerum-based molecular biomarkers may enable earlier risk stratification in children presenting with dilated cardiomyopathy. C_LIO_LIMulti-omic integration may improve identification of pediatric patients at risk for transplantation, mechanical circulatory support, or death. C_LIO_LIThese findings support further validation of circulating biomarker panels to guide personalized management in this rare disease. C_LI RESEARCH PERSPECTIVEWhat New Question Does This Study Raise? O_LICan integrated circulating miRNA-protein signatures identify biologically distinct trajectories of recovery versus progression in children with dilated cardiomyopathy? C_LIO_LIDo circulating molecular profiles reflect underlying disease mechanisms that determine divergent clinical outcomes in pediatric DCM? C_LI What Question Should Be Addressed Next? O_LIDo the pathways identified by integrated miRNA-protein analysis (fibrosis, remodeling, and inflammation) play causal roles in determining recovery versus progression? C_LIO_LICan multi-omic biomarkers be incorporated into prospective studies to improve early risk stratification and guide clinical management? C_LI