{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T02:44:43Z","timestamp":1774406683435,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,7]]},"group-title":"Molecular Biology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T00:00:00Z","timestamp":1749254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["K24HL150630"],"award-info":[{"award-number":["K24HL150630"]}]},{"name":"NIH","award":["R01HL156670"],"award-info":[{"award-number":["R01HL156670"]}]},{"name":"NIH","award":["K25HL148386"],"award-info":[{"award-number":["K25HL148386"]}]},{"name":"Colorado CTSA Grant","award":["UL1 TR002535"],"award-info":[{"award-number":["UL1 TR002535"]}]},{"name":"Jack Cooper Millisor Chair in Pediatric Heart Disease"},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["24DIVSUP1281949"],"award-info":[{"award-number":["24DIVSUP1281949"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["25PRE1375864"],"award-info":[{"award-number":["25PRE1375864"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["23CDA1052411"],"award-info":[{"award-number":["23CDA1052411"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ludeman Family Center for Women\u2019s Health Research seed grant"},{"name":"The generous grants of John Patrick Albright"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Therapies for pediatric idiopathic dilated cardiomyopathy (iDCM) are extrapolated from adult heart failure despite limited efficacy, suggesting fundamental biological differences. Our prior transcriptomic studies indicate activation of developmental signaling pathways, including Notch and WNT, in pediatric iDCM; however, their mechanistic contribution remains unknown. We tested whether reactivation of Notch and WNT\/\u03b2-catenin signaling drives pathological remodeling in postnatal hearts and whether pathway inhibition improves cardiac function.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We developed a juvenile rat model to reproduce age-dependent molecular features of pediatric iDCM using \u03b2-adrenergic stimulation (isoproterenol, ISO) and secreted frizzled-related protein-1 (sFRP1), a circulating WNT modulator elevated in children with DCM. Cardiac function was assessed by echocardiography; pathway activation by immunoblotting and transcriptomics; myocardial stiffness by atomic force microscopy. Findings were compared with explanted pediatric and adult human myocardium.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Explanted pediatric, but not adult iDCM hearts exhibited increased nuclear and cytoplasmic Notch intracellular domain (NICD) and \u03b2-catenin. Combined ISO and sFRP1 treatment recapitulated key features of pediatric disease, including ventricular dilation, reduced ejection fraction, reactivation of the fetal gene program, and increased myocardial stiffness in the absence of fibrosis or hypertrophy. Bulk and single-nucleus RNA sequencing identified cardiomyocyte-specific activation of Notch and WNT pathways and reduced intercellular signaling diversity. Mechanistically, \u03b2-catenin silencing attenuated Notch target gene activation and pathological remodeling\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Pharmacologic Notch inhibition reduced NICD and \u03b2-catenin accumulation, improved ventricular function, and normalized myocardial stiffness\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Pediatric iDCM is characterized by pathological co-activation of developmental Notch\u2013WNT signaling pathways that are not observed in adult disease. Reactivation of this axis promotes maladaptive remodeling and myocardial stiffening, and its inhibition improves cardiac function. These findings establish developmental signaling reactivation as a central mechanism of pediatric iDCM and support age-specific therapeutic strategies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.07.658396","type":"posted-content","created":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:45:10Z","timestamp":1749343510000},"source":"Crossref","is-referenced-by-count":1,"title":["Synergistic Notch\u2013WNT Activation Underlies Pediatric Dilated Cardiomyopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9184-6965","authenticated-orcid":false,"given":"Obed O.","family":"Nyarko","sequence":"first","affiliation":[{"name":"Integrative Physiology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ethan","family":"Rausch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared R.H.","family":"Goff","sequence":"additional","affiliation":[{"name":"University of Utah Department of Internal Medicine."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4249-4363","authenticated-orcid":false,"given":"Anis","family":"Karimpour-Fard","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlyn S.","family":"Conard","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Hernandez-Lagunas","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"McKenna P.A.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-4698","authenticated-orcid":false,"given":"Michael R.","family":"Bristow","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph C.","family":"Cleveland","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew L.","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4224-6626","authenticated-orcid":false,"given":"Brisa","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"},{"name":"Bioengineering Department, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8029-981X","authenticated-orcid":false,"given":"Shelley D.","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3418-7750","authenticated-orcid":false,"given":"Brian L.","family":"Stauffer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0349-1776","authenticated-orcid":false,"given":"Carmen C.","family":"Sucharov","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, 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