{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:19:03Z","timestamp":1790425143666,"version":"4.1.0"},"reference-count":117,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,13]],"date-time":"2021-06-13T00:00:00Z","timestamp":1623542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide association studies have shown that small variations in genetic regions are key to the expression of these transcription factors and thereby modulate the electrical function of the heart. Moreover, mutations in these factors are found in arrhythmogenic pathologies such as congenital atrioventricular block, as well as in specific forms of atrial fibrillation and ventricular tachycardia. In this review, we discuss the developmental origin of distinct electrophysiological structures in the heart and their involvement in cardiac arrhythmias.<\/jats:p>","DOI":"10.3390\/jcdd8060070","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:30:25Z","timestamp":1623666625000},"page":"70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["How Cardiac Embryology Translates into Clinical Arrhythmias"],"prefix":"10.3390","volume":"8","author":[{"given":"Mathilde R.","family":"Rivaud","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Blok","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Embryology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-0418","authenticated-orcid":false,"given":"Monique R. M.","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Embryology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands"},{"name":"Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastiaan J.","family":"Boukens","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.cell.2005.08.004","article-title":"The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient","volume":"123","author":"Costantini","year":"2005","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/CIRCRESAHA.117.310959","article-title":"The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity","volume":"121","author":"Veerman","year":"2017","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1136\/jmg.2008.061002","article-title":"20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits","volume":"46","author":"Lalani","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.ejmg.2008.07.012","article-title":"A 8.26Mb deletion in 6q16 and a 4.95Mb deletion in 20p12 including JAG1 and BMP2 in a patient with Alagille syndrome and Wolff-Parkinson-White syndrome","volume":"51","author":"Le","year":"2008","journal-title":"Eur.J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1073\/pnas.96.6.2919","article-title":"Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations","volume":"96","author":"Basson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.109.204123","article-title":"Specification of the cardiac conduction system by transcription factors","volume":"105","author":"Hatcher","year":"2009","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1126\/science.281.5373.108","article-title":"Congenital heart disease caused by mutations in the transcription factor NKX2-5","volume":"281","author":"Schott","year":"1998","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrg1710","article-title":"Building the mammalian heart from two sources of myocardial cells","volume":"6","author":"Buckingham","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/CIRCRESAHA.109.205419","article-title":"Development of the pacemaker tissues of the heart","volume":"106","author":"Christoffels","year":"2010","journal-title":"Circ. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/01.RES.71.2.240","article-title":"Persisting zones of slow impulse conduction in developing chicken hearts","volume":"71","author":"Opthof","year":"1992","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0002-8703(39)90597-1","article-title":"The development of the electrocardiogram of the embryonic heart","volume":"17","author":"Hoff","year":"1939","journal-title":"Am. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S1534-5807(01)00040-5","article-title":"The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm","volume":"1","author":"Kelly","year":"2001","journal-title":"Dev. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1152\/physrev.00006.2003","article-title":"Cardiac chamber formation: Development, genes, and evolution","volume":"83","author":"Moorman","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1113\/jphysiol.2014.279380","article-title":"Misinterpretation of the mouse ECG: \u201cmusing the waves of Mus musculus","volume":"592","author":"Boukens","year":"2014","journal-title":"\u201d J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1161\/CIRCULATIONAHA.110.980607","article-title":"Formation of the building plan of the human heart: Morphogenesis, growth, and differentiation","volume":"123","author":"Sizarov","year":"2011","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1161\/01.RES.0000258019.74591.b3","article-title":"Molecular pathway for the localized formation of the sinoatrial node","volume":"100","author":"Mommersteeg","year":"2007","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.diff.2012.04.006","article-title":"Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult","volume":"84","author":"Jongbloed","year":"2012","journal-title":"Differentiation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1161\/CIRCRESAHA.112.271064","article-title":"Lineage tree for the venous pole of the heart: Clonal analysis clarifies controversial genealogy based on genetic tracing","volume":"111","author":"Lescroart","year":"2012","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1161\/CIRCRESAHA.107.161182","article-title":"Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium","volume":"101","author":"Mommersteeg","year":"2007","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.ijcard.2008.11.098","article-title":"Pulmonary vein and atrial wall pathology in human total anomalous pulmonary venous connection","volume":"134","author":"Douglas","year":"2009","journal-title":"Int. J. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1017\/S1047951101000993","article-title":"Development of the human pulmonary vein and its incorporation in the morphologically left atrium","volume":"11","author":"Webb","year":"2001","journal-title":"Cardiol. Young"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.amjcard.2005.11.019","article-title":"Histology of vascular myocardial wall of left atrial body after pulmonary venous incorporation","volume":"97","author":"Douglas","year":"2006","journal-title":"Am. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S0008-6363(02)00490-X","article-title":"Tissue structure and connexin expression of canine pulmonary veins","volume":"55","author":"Verheule","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1113\/jphysiol.2003.046417","article-title":"Cellular electrophysiology of canine pulmonary vein cardiomyocytes: Action potential and ionic current properties","volume":"551","author":"Ehrlich","year":"2003","journal-title":"J. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cardiores.2004.08.014","article-title":"Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium","volume":"65","author":"Melnyk","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mcna.2007.09.002","article-title":"Status of the epidemiology of atrial fibrillation","volume":"92","author":"Kannel","year":"2008","journal-title":"Med. Clin. North Am."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1056\/NEJM199809033391003","article-title":"Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins","volume":"339","author":"Haissaguerre","year":"1998","journal-title":"New Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/S0008-6363(02)00258-4","article-title":"Electrical, contractile and structural remodeling during atrial fibrillation","volume":"54","author":"Allessie","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.jacep.2021.01.011","article-title":"The Blinding Period Following Ablation Therapy for Atrial Fibrillation: Proarrhythmic and Antiarrhythmic Pathophysiological Mechanisms","volume":"7","author":"Gottlieb","year":"2021","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1046\/j.1540-8167.2003.03075.x","article-title":"Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation","volume":"14","author":"McMahon","year":"2003","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_31","first-page":"133","article-title":"Node-like cells in the myocardial layer of the pulmonary vein of rats: An ultrastructural study","volume":"145","author":"Masani","year":"1986","journal-title":"J. Anat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/HCO.0b013e3282fa7142","article-title":"Atrial fibrillation: Evidence for genetically determined disease","volume":"23","author":"Andalib","year":"2008","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/sj.ejhg.5201702","article-title":"A novel CSX\/NKX2-5 mutation causes autosomal-dominant AV block: Are atrial fibrillation and syncopes part of the phenotype?","volume":"14","author":"De","year":"2006","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nature06007","article-title":"Variants conferring risk of atrial fibrillation on chromosome 4q25","volume":"448","author":"Gudbjartsson","year":"2007","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature17959","article-title":"Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury","volume":"534","author":"Tao","year":"2016","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1161\/CIRCGENETICS.110.958116","article-title":"PITX2 Insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis","volume":"4","author":"Chinchilla","year":"2011","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nadadur, R.D., Broman, M.T., Boukens, B., Mazurek, S.R., Yang, X., Van Den Boogaard, M., Bekeny, J., Gadek, M., Ward, T., and Zhang, M. (2016). Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Sci. Transl. Med., 8.","DOI":"10.1126\/scitranslmed.aaf4891"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e001902","DOI":"10.1161\/CIRCGENETICS.117.001902","article-title":"Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential","volume":"10","author":"Tucker","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bossada, F., Rivaud, M., Christoffels, V., and Boukens, B.J.D. (2021). Noncoding region regulates Prrx1 and predisposes to atrial arrhythmias. Circ. Res.","DOI":"10.1093\/eurheartj\/ehab724.3310"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1161\/CIRCULATIONAHA.113.005421","article-title":"Driver domains in persistent atrial fibrillation","volume":"130","author":"Haissaguerre","year":"2014","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1172\/JCI44350","article-title":"Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice","volume":"121","author":"Aanhaanen","year":"2011","journal-title":"J. Clin. Invest."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1161\/01.RES.0000169271.33675.05","article-title":"Functional properties of mouse connexin30.2 expressed in the conduction system of the heart","volume":"96","author":"Kreuzberg","year":"2005","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1242\/dev.038562","article-title":"Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay","volume":"136","author":"Munshi","year":"2009","journal-title":"Development"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/bdra.20826","article-title":"Origin and development of the atrioventricular myocardial lineage: Insight into the development of accessory pathways","volume":"91","author":"Aanhaanen","year":"2011","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1101\/gad.416007","article-title":"Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria","volume":"21","author":"Hoogaars","year":"2007","journal-title":"Genes Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5601","DOI":"10.1242\/dev.02156","article-title":"Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning","volume":"132","author":"Ma","year":"2005","journal-title":"Development"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1161\/CIRCRESAHA.116.304731","article-title":"Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties","volume":"116","author":"Gillers","year":"2015","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/ng.511","article-title":"Several common variants modulate heart rate, PR interval and QRS duration","volume":"42","author":"Holm","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/ng.517","article-title":"Genome-wide association study of PR interval","volume":"42","author":"Pfeufer","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ng.716","article-title":"Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction","volume":"42","author":"Sotoodehnia","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/jdb2010001","article-title":"The Epicardium and the Development of the Atrioventricular Junction in the Murine Heart","volume":"2","author":"Lockhart","year":"2014","journal-title":"J. Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1161\/01.RES.78.1.110","article-title":"The development of the atrioventricular junction in the human heart","volume":"78","author":"Wessels","year":"1996","journal-title":"Circ. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1161\/CIRCRESAHA.110.222992","article-title":"Developmental origin, growth, and three-dimensional architecture of the atrioventricular conduction axis of the mouse heart","volume":"107","author":"Aanhaanen","year":"2010","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1161\/CIRCRESAHA.108.192450","article-title":"The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle","volume":"104","author":"Aanhaanen","year":"2009","journal-title":"Circ. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/0012-1606(80)90496-0","article-title":"The development of the conduction system in the mouse embryo heart","volume":"80","author":"Viragh","year":"1980","journal-title":"Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1172\/JCI19846","article-title":"Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system","volume":"113","author":"Jay","year":"2004","journal-title":"J. Clin. Invest."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.1242\/dev.01265","article-title":"The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system","volume":"131","author":"Moskowitz","year":"2004","journal-title":"Development"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1172\/JCI44470","article-title":"Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways","volume":"121","author":"Rentschler","year":"2011","journal-title":"J. Clin. Invest."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.yjmcc.2010.12.017","article-title":"Molecular architecture of the human specialised atrioventricular conduction axis","volume":"50","author":"Greener","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/j.1540-8167.1993.tb01245.x","article-title":"\u201cAV nodal\u201d reentry: Part II: AV nodal, AV junctional, or atrionodal reentry?","volume":"4","author":"McGuire","year":"1993","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1161\/CIRCRESAHA.108.172403","article-title":"Computer three-dimensional reconstruction of the atrioventricular node","volume":"102","author":"Li","year":"2008","journal-title":"Circ. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1111\/jcmm.12525","article-title":"The sinus venosus myocardium contributes to the atrioventricular canal: Potential role during atrioventricular node development?","volume":"19","author":"Kelder","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1111\/j.1540-8159.2011.03150.x","article-title":"The 11th World Survey of Cardiac Pacing and Implantable Cardioverter-Defibrillators: Calendar Year 2009-A World Society of Arrhythmia\u2019s Project","volume":"34","author":"Mond","year":"2011","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.hrthm.2009.04.001","article-title":"Paroxysmal atrioventricular block","volume":"6","author":"Lee","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1136\/heartjnl-2012-303220","article-title":"Vagally mediated atrioventricular block: Pathophysiology and diagnosis","volume":"99","author":"Alboni","year":"2013","journal-title":"Heart"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/ng.516","article-title":"Genetic variation in SCN10A influences cardiac conduction","volume":"42","author":"Chambers","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"van Weerd, J.H., Mohan, R.A., van Duijvenboden, K., Hooijkaas, I.B., Wakker, V., Boukens, B.J., Barnett, P., and Christoffels, V.M. (2020). Trait-associated noncoding variant regions affect TBX3 regulation and cardiac conduction. Elife, 9.","DOI":"10.7554\/eLife.56697"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"E154","DOI":"10.1073\/pnas.1115165109","article-title":"Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis","volume":"109","author":"Frank","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"18617","DOI":"10.1073\/pnas.1919379117","article-title":"T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system","volume":"117","author":"Mohan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1152\/physrev.1988.68.2.608","article-title":"Morphology and electrophysiology of the mammalian atrioventricular node","volume":"68","author":"Meijler","year":"1988","journal-title":"Physiol. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1540-8167.2006.00522.x","article-title":"Atrioventricular nodal reentrant tachycardia in two siblings with Wolfram syndrome","volume":"17","author":"Frisch","year":"2006","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1540-8159.2004.00388.x","article-title":"Familial atrioventricular nodal reentry tachycardia","volume":"27","author":"Hayes","year":"2004","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/S0008-6363(96)00011-9","article-title":"Mahaim, Kent and abnormal atrioventricular conduction","volume":"31","author":"Anderson","year":"1996","journal-title":"Cardiovasc. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S0735-1097(85)80095-4","article-title":"Wolff-Parkinson-White syndrome and supraventricular tachycardia during infancy: Management and follow-up","volume":"5","author":"Deal","year":"1985","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1113\/jphysiol.2013.259598","article-title":"Brief history of arrhythmia in the WPW syndrome\u2014The contribution of George Ralph Mines","volume":"591","author":"Boukens","year":"2013","journal-title":"J. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1161\/01.RES.0000162000.03997.65","article-title":"Development of the right ventricular inflow tract and moderator band: A possible morphological and functional explanation for Mahaim tachycardia","volume":"96","author":"Jongbloed","year":"2005","journal-title":"Circ. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1161\/CIRCULATIONAHA.107.696583","article-title":"Abnormal conduction and morphology in the atrioventricular node of mice with atrioventricular canal targeted deletion of Alk3\/Bmpr1a receptor","volume":"116","author":"Stroud","year":"2007","journal-title":"Circulation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1161\/01.RES.0000262688.14288.b8","article-title":"Trabeculated right ventricular free wall in the chicken heart forms by ventricularization of the myocardium initially forming the outflow tract","volume":"100","author":"Rana","year":"2007","journal-title":"Circ. Res."},{"key":"ref_79","first-page":"661","article-title":"Experimental study of the development of the truncus and the conus in the chick embryo","volume":"123","author":"Sanchez","year":"1977","journal-title":"J. Anat."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1161\/CIRCRESAHA.108.172189","article-title":"The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning","volume":"103","author":"Dandonneau","year":"2008","journal-title":"Circ. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1161\/CIRCRESAHA.115.305020","article-title":"Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart","volume":"115","author":"Rana","year":"2014","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1161\/CIRCULATIONAHA.110.953844","article-title":"Three-dimensional and molecular analysis of the venous pole of the developing human heart","volume":"122","author":"Sizarov","year":"2010","journal-title":"Circulation"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Boukens, B.J., Sylva, M., De Gier-De Vries, C., Remme, C.A., Bezzina, C.R., Christoffels, V.M., and Coronel, R. (2013). Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. Circ. Res., 113.","DOI":"10.1161\/CIRCRESAHA.113.301565"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1161\/CIRCRESAHA.108.188698","article-title":"Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias","volume":"104","author":"Boukens","year":"2009","journal-title":"Circ. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1161\/CIRCULATIONAHA.110.972612","article-title":"Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium","volume":"123","author":"Nademanee","year":"2011","journal-title":"Circulation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.joa.2016.07.002","article-title":"J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge","volume":"32","author":"Antzelevitch","year":"2016","journal-title":"J. Arrhythm."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"H1553","DOI":"10.1152\/ajpheart.00459.2013","article-title":"Measurement and interpretation of electrocardiographic QT intervals in murine hearts","volume":"306","author":"Zhang","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ten Sande, J.N., Coronel, R., Conrath, C.E., Driessen, A.H., de Groot, J.R., Tan, H.L., Nademanee, K., Wilde, A.A., de Bakker, J.M., and van Dessel, P.F. (2015). ST-Segment Elevation and Fractionated Electrograms in Brugada Syndrome Patients Arise from the Same Structurally Abnormal Subepicardial RVOT Area but Have a Different Mechanism. Circ. Arrhythm. Electrophysiol.","DOI":"10.1161\/CIRCEP.115.003366"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1161\/hc5001.100834","article-title":"Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family","volume":"104","author":"Kyndt","year":"2001","journal-title":"Circulation"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1161\/CIRCULATIONAHA.105.532614","article-title":"Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study","volume":"112","author":"Coronel","year":"2005","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1161\/CIRCULATIONAHA.105.520999","article-title":"Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome","volume":"112","author":"Frustaci","year":"2005","journal-title":"Circulation"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1161\/CIRCEP.108.790543","article-title":"Slow and discontinuous conduction conspire in Brugada syndrome: A right ventricular mapping and stimulation study","volume":"1","author":"Postema","year":"2008","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.hrthm.2010.09.066","article-title":"ST segment elevation by current-to-load mismatch: An experimental and computational study","volume":"8","author":"Hoogendijk","year":"2011","journal-title":"Heart Rhythm"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.hrthm.2009.10.007","article-title":"Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch","volume":"7","author":"Hoogendijk","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1161\/CIRCEP.110.937029","article-title":"The Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome","volume":"3","author":"Hoogendijk","year":"2010","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.hrthm.2015.11.014","article-title":"Embryonic development of the right ventricular out fl ow tract and arrhythmias","volume":"13","author":"Boukens","year":"2016","journal-title":"Heart Rhythm"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Blok, M., and Boukens, B.J. (2020). Mechanisms of Arrhythmias in the Brugada Syndrome. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197051"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/eurheartj\/ehaa1051","article-title":"Brugada syndrome and reduced right ventricular outflow tract conduction reserve: A final common pathway?","volume":"42","author":"Behr","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1016\/j.jacc.2015.08.862","article-title":"Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome","volume":"66","author":"Nademanee","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1016\/j.jacc.2007.01.085","article-title":"Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias","volume":"49","author":"Kim","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrcardio.2015.121","article-title":"Mechanism, diagnosis, and treatment of outflow tract tachycardia","volume":"12","author":"Lerman","year":"2015","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1016\/j.hrthm.2009.06.017","article-title":"Arrhythmias originating from the right ventricular outflow tract: How to distinguish \u201cmalignant\u201d from \u201cbenign\u201d?","volume":"6","author":"Shimizu","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s11427-012-4265-3","article-title":"L-type calcium current in right ventricular outflow tract myocytes of rabbit heart","volume":"55","author":"Liang","year":"2012","journal-title":"Sci. China Life Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1111\/jcmm.12329","article-title":"Distinctive electrophysiological characteristics of right ventricular out-flow tract cardiomyocytes","volume":"18","author":"Lu","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.bpj.2010.06.042","article-title":"So little source, so much sink: Requirements for afterdepolarizations to propagate in tissue","volume":"99","author":"Xie","year":"2010","journal-title":"Biophys. J."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.pharmthera.2013.04.010","article-title":"Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues","volume":"139","author":"Dobrzynski","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1161\/CIRCEP.113.001347","article-title":"Ubiquitous myocardial extensions into the pulmonary artery demonstrated by integrated intracardiac echocardiography and electroanatomic mapping: Changing the paradigm of idiopathic right ventricular outflow tract arrhythmias","volume":"7","author":"Liu","year":"2014","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1161\/01.CIR.0000095026.19339.BB","article-title":"Idiopathic left bundle-branch block-shaped ventricular tachycardia may originate above the pulmonary valve","volume":"108","author":"Timmermans","year":"2003","journal-title":"Circulation"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"S163","DOI":"10.1111\/j.1540-8159.2005.00010.x","article-title":"Sympathovagal balance prior to onset of repetitive monomorphic idiopathic ventricular tachycardia","volume":"28","author":"Zimmermann","year":"2005","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1253\/jcj.62.745","article-title":"Heart rate variability before spontaneous episodes of ventricular tachycardia originating from right ventricular outflow tract in patients without organic heart disease","volume":"62","author":"Yoshida","year":"1998","journal-title":"Jpn. Circ. J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1111\/j.1540-8159.1997.tb06073.x","article-title":"Role of sympathovagal balance in the initiation of idiopathic ventricular tachycardia originating from right ventricular outflow tract","volume":"20","author":"Hayashi","year":"1997","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.12659\/MSM.900143","article-title":"Increased Local Sympathetic Nerve Activity During Pathogenesis of Ventricular Arrhythmias Originating from the Right Ventricular Outflow Tract","volume":"23","author":"Wang","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.autneu.2018.03.006","article-title":"The autonomic neural mechanism of right ventricular outflow tract tachycardia","volume":"212","author":"Chang","year":"2018","journal-title":"Auton. Neurosci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1161\/01.CIR.98.15.1525","article-title":"Localization of optimal ablation site of idiopathic ventricular tachycardia from right and left ventricular outflow tract by body surface ECG","volume":"98","author":"Kamakura","year":"1998","journal-title":"Circulation"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1161\/01.CIR.92.3.421","article-title":"Mechanism of repetitive monomorphic ventricular tachycardia","volume":"92","author":"Lerman","year":"1995","journal-title":"Circulation"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1111\/j.1540-8167.2006.00539.x","article-title":"Right and left ventricular outflow tract tachycardias: Evidence for a common electrophysiologic mechanism","volume":"17","author":"Iwai","year":"2006","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1540-8159.2009.02606.x","article-title":"Transcriptional profiling of septal wall of the right ventricular outflow tract in patients with idiopathic ventricular arrhythmias","volume":"33","author":"Hasdemir","year":"2010","journal-title":"Pacing Clin. Electrophysiol."}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/8\/6\/70\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:51Z","timestamp":1760163231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/8\/6\/70"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,13]]},"references-count":117,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["jcdd8060070"],"URL":"https:\/\/doi.org\/10.3390\/jcdd8060070","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,13]]}}}