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• W2895888799 abstract "HomeCirculationVol. 138, No. Suppl_1Abstract 10344: Transcriptional Patterning of the Cardiac Conduction System Prevents Arrhythmias Free AccessAbstractAboutSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractElectrophysiology and ArrhythmiasSession Title: Arrhythmias in Experimental Models Session IIAbstract 10344: Transcriptional Patterning of the Cardiac Conduction System Prevents Arrhythmias Ozanna Burnicka-Turek, Michael T Broman, Jeffrey D Steimle, Bastiaan J Boukens, Kohta Ikegami, Yun Qiao, David E Arnolds, Rangarajan D Nadadaru, Xinan H Yang, Vickas V Patel, Marcelo A Nobrega, Michael J Rust, Igor R Efimov and Ivan P Moskowitz Ozanna Burnicka-TurekOzanna Burnicka-Turek Search for more papers by this author , Michael T BromanMichael T Broman Search for more papers by this author , Jeffrey D SteimleJeffrey D Steimle Search for more papers by this author , Bastiaan J BoukensBastiaan J Boukens Search for more papers by this author , Kohta IkegamiKohta Ikegami Search for more papers by this author , Yun QiaoYun Qiao Search for more papers by this author , David E ArnoldsDavid E Arnolds Search for more papers by this author , Rangarajan D NadadaruRangarajan D Nadadaru Search for more papers by this author , Xinan H YangXinan H Yang Search for more papers by this author , Vickas V PatelVickas V Patel Search for more papers by this author , Marcelo A NobregaMarcelo A Nobrega Search for more papers by this author , Michael J RustMichael J Rust Search for more papers by this author , Igor R EfimovIgor R Efimov Search for more papers by this author and Ivan P MoskowitzIvan P Moskowitz Search for more papers by this author Originally published15 Oct 2018https://doi.org/10.1161/circ.138.suppl_1.10344Circulation. 2018;138:A10344AbstractThe cardiac conduction system (CCS) is a specialized network of cardiomyocytes that organizes cardiac contraction. Patterning of the CCS into atrial nodal and ventricular conduction system (VCS) components with distinct physiology has been recognized for more than a century. While the distinctions between these components are essential for the normal heartbeat, the mechanisms establishing and maintaining these differences remain poorly understood. Using mouse genetics, we found that adult specific removal of a single gene, Tbx5, encoding a T-box transcriptional activator, caused conversion of the VCS into a nodal-like component based on molecular, cellular and functional criteria. Expression analysis showed a loss of VCS-specific transcriptional network required for fast conduction and the VCS-specific myocardial action potential. In contrast, genes required for the slow conducting nodal phenotype were maintained. Action potentials (APs) of Tbx5-deficient VCS myocytes demonstrated a nodal-like morphology characterized by significant increase in AP duration and reductions in INa and IK1currents. Moreover, the VCS-specific loss of functional Tbx5 induced cellular automaticity in VCS cardiomyocytes that initiated lethal ventricular arrhythmias. VCS-specific overexpression of Tbx3, encoding a T-box transcriptional repressor, similarly re-patterned the fast VCS into a slow, nodal-like system, suggesting a T-box rheostat mechanism confirmed by genetic interaction studies. TBX5 bound and directly activated cis-regulatory elements at fast conduction loci, defining the identity of the adult VCS. Furthermore, cis-regulatory elements at Tbx5 itself were T-box dependent, resulting in positive feedback on Tbx5 expression. Modeling suggested that this higher-ordered gene regulatory network (GRN) architecture fortifies fast versus slow conduction regional identities for cardiac rhythm homeostasis. Thus, the entire CCS is patterned with a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network locally driven specifically in the VCS. Disruptions of the fast VCS GRN allow the nodal ground state to emerge, providing a molecular mechanism for some lethal ventricular arrhythmias.FootnotesAuthor Disclosures: O. Burnicka-Turek: None. M.T. Broman: None. J.D. Steimle: None. B.J. Boukens: None. K. Ikegami: None. Y. Qiao: None. D.E. Arnolds: None. R.D. Nadadaru: None. X.H. Yang: None. V.V. Patel: None. M.A. Nobrega: None. M.J. Rust: None. I.R. Efimov: None. I.P. Moskowitz: None. eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails November 6, 2018Vol 138, Issue Suppl_1 Advertisement Article InformationMetrics © 2018 by American Heart Association, Inc.https://doi.org/10.1161/circ.138.suppl_1.10344 Originally publishedOctober 15, 2018 KeywordsIon channelsVentricular arrhythmiaSudden cardiac deathHeart conduction systemArrhythmia mapping Advertisement" @default.
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