{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T15:07:25Z","timestamp":1774364845800,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Systems Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pediatric 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    miRNAs were identified by RNA-seq, whereas proteins were identified by SomaScan\n                    <jats:sup>\u00ae<\/jats:sup>\n                    . 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Thirty 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Circulating 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CLINICAL PERSPECTIVE<\/jats:title>\n                  <jats:p>\n                    <jats:bold>What Is New?<\/jats:bold>\n                  <\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Circulating miRNA and protein profiles measured at presentation distinguish children with pediatric DCM who recover from those who progress to advanced heart failure.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>A combined multi-omic biomarker demonstrated strong discriminatory performance in this cohort (AUC 0.92).<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Pathway analysis implicates extracellular matrix remodeling, fibrosis, and inflammatory signaling in children with adverse clinical trajectories.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>\n                    <jats:bold>What Are the Clinical Implications?<\/jats:bold>\n                  <\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Serum-based molecular biomarkers may enable earlier risk stratification in children presenting with dilated cardiomyopathy.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Multi-omic integration may improve identification of pediatric patients at risk for transplantation, mechanical circulatory support, or death.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These findings support further validation of circulating biomarker panels to guide personalized management in this rare disease.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESEARCH PERSPECTIVE<\/jats:title>\n                  <jats:p>\n                    <jats:bold>What New Question Does This Study Raise?<\/jats:bold>\n                  <\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Can integrated circulating miRNA\u2013protein signatures identify biologically distinct trajectories of recovery versus progression in children with dilated cardiomyopathy?<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Do circulating molecular profiles reflect underlying disease mechanisms that determine divergent clinical outcomes in pediatric DCM?<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>\n                    <jats:bold>What Question Should Be Addressed Next?<\/jats:bold>\n                  <\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Do the pathways identified by integrated miRNA\u2013protein analysis (fibrosis, remodeling, and inflammation) play causal roles in determining recovery versus progression?<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Can multi-omic biomarkers be incorporated into prospective studies to improve early risk stratification and guide clinical management?<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                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