{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:52:39Z","timestamp":1774277559022,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Cardiovascular Medicine","reference-count":55,"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":[[2026,3,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Current management of pediatric dilated cardiomyopathy (DCM) in children relies on guideline-directed medical therapy (GDMT) extrapolated from adult heart failure. However, due to small sample size, randomized trials of GDMT agents in children have failed to demonstrate efficacy and mortality benefits seen in adults, suggesting fundamental differences in disease mechanisms. We hypothesized that distinct age-dependent transcriptional programs underlie this therapeutic discordance.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed comparative transcriptomic profiling using bulk RNA sequencing on explanted left ventricular tissue from pediatric (n=29) and adult (n=35) DCM patients (adult DCM from previously published data) compared with age-matched non-failing controls (n=22 pediatric, 14 adult). We analyzed differential gene expressions, pathway enrichment across disease etiologies, and the regulation of a conserved 430-gene \u03b21-adrenergic receptor gene signaling network (\u03b21-GSN) known to modulate remodeling in adult heart failure.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Transcriptional signatures were profoundly distinct, with only 7.4% of differentially expressed genes shared between adult and pediatric cohorts. Pediatric DCM was characterized by transcriptional reprogramming and the activation of developmental pathways, including WNT\/\u03b2-catenin and Notch signaling. Conversely, adult DCM hearts were enriched for pathways associated with metabolic dysfunction, mitochondrial deficits, and inflammation. Crucially, while the \u03b21-GSN was desensitized and extensively remodeled in adults, the pathway remained activated in children, with only 4 of 430 network genes showing antithetical regulation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The lack of pathological \u03b2-adrenergic remodeling in children could provide a molecular explanation for the lack of clear efficacy of \u03b2-blockers in this population. Collectively, these results suggest pediatric DCM represents a biologically distinct disease entity rather than an earlier manifestation of adult heart failure, and future therapeutic strategies must move beyond adult extrapolation to target pediatric-specific pathways.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is New?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>This comparative transcriptomic analysis demonstrates that pediatric and adult dilated cardiomyopathy possess profoundly distinct biological signatures, with only 7.4% of differentially expressed disease-associated genes shared between the two age groups.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Unlike adult dilated cardiomyopathy, which is driven by metabolic dysfunction and extensive remodeling of the \u03b21-adrenergic receptor gene signaling network, pediatric disease is uniquely characterized by the activation of developmental pathways such as WNT\/\u03b2-catenin and Notch signaling without significant pathological \u03b21-adrenergic remodeling.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What Are the Clinical Implications?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>The absence of pathological \u03b2-adrenergic remodeling in pediatric hearts provides a molecular explanation for the limited clinical efficacy of \u03b2-blocker therapy in this population, underscoring the critical need to develop age-specific precision medicine strategies rather than continuing to extrapolate guideline-directed medical therapies from adult heart failure.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.17.26348665","type":"posted-content","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T02:50:24Z","timestamp":1774061424000},"source":"Crossref","is-referenced-by-count":0,"title":["Age-dependent Transcriptional Programs Distinguish Pediatric from Adult Dilated Cardiomyopathy"],"prefix":"10.64898","author":[{"given":"Zoe","family":"Leroux","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Obed O.","family":"Nyarko","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University 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