{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:09:28Z","timestamp":1785521368925,"version":"3.56.0"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2017,8,18]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (inducible Notch intracellular domain [iNICD]). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including\n              <jats:italic>Nkx2-5<\/jats:italic>\n              (NK2 homeobox 5),\n              <jats:italic>Tbx3<\/jats:italic>\n              , and\n              <jats:italic>Tbx5<\/jats:italic>\n              are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including\n              <jats:italic>Scn5a<\/jats:italic>\n              (Nav1.5) and\n              <jats:italic>Gja5<\/jats:italic>\n              (connexin 40), are persistently downregulated long after a transient Notch pulse. Consistent with the reduction in\n              <jats:italic>Scn5a<\/jats:italic>\n              transcript, Notch induces global changes in the atrial action potential, including a reduced\n              <jats:italic>dV<\/jats:italic>\n              <jats:sub>m<\/jats:sub>\n              <jats:italic>\/dt<\/jats:italic>\n              <jats:sub>max<\/jats:sub>\n              . In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology and predisposes to an arrhythmogenic substrate.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes, resulting in sinus bradycardia, sinus pauses, and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.310396","type":"journal-article","created":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T00:50:18Z","timestamp":1499129418000},"page":"549-563","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice"],"prefix":"10.1161","volume":"121","author":[{"given":"Yun","family":"Qiao","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Lipovsky","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Hicks","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somya","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Khandekar","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Guzy","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kel Vin","family":"Woo","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor R.","family":"Efimov","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology 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