title: Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias.
abstract: CHF1/Hey2 is a Notch-responsive basic helix-loop-helix transcription factor involved in cardiac development. Common variants in Hey2 are associated with Brugada syndrome. We hypothesized that absence of CHF1/Hey2 would result in abnormal cellular electrical activity, altered cardiac conduction system (CCS) development, and increased arrhythmogenesis. We isolated neonatal CHF/Hey2-knockout (KO) cardiac myocytes and measured action potentials and ion channel subunit gene expression. We also crossed myocardial-specific CHF1/Hey2-KO mice with cardiac conduction system LacZ reporter mice and stained for conduction system tissue. We also performed ambulatory ECG monitoring for arrhythmias and heart rate variability. Neonatal cardiomyocytes from CHF1/Hey2-KO mice demonstrate a 50% reduction in action potential dV/dT, a 50-75% reduction in SCN5A, KCNJ2, and CACNA1C ion channel subunit gene expression, and an increase in delayed afterdepolarizations from 0/min to 12/min. CHF1/Hey2 cKO CCS-lacZ mice have a ∼3-fold increase in amount of CCS tissue. Ambulatory ECG monitoring showed no difference in cardiac conduction, arrhythmias, or heart rate variability. Wild-type cells or animals were used in all experiments. CHF1/Hey2 may contribute to Brugada syndrome by influencing the expression of SCN5A and formation of the cardiac conduction system, but its absence does not cause baseline conduction defects or arrhythmias in the adult mouse.-Hartman, M. E., Liu, Y., Zhu, W.-Z., Chien, W.-M., Weldy, C. S., Fishman, G. I., Laflamme, M. A., Chin, M. T. Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias.
authors.affiliation: Division of Cardiology, Department of Medicine, and.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hartman
authors.affiliation: Division of Cardiology, Department of Medicine, and.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, Washington, USA; and.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
authors.affiliation: Division of Cardiology, Department of Medicine, and.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chien
authors.affiliation: Division of Cardiology, Department of Medicine, and.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Weldy
authors.affiliation: The Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.affiliation: Department of Pathology, Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, Washington, USA; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
authors.affiliation: Division of Cardiology, Department of Medicine, and Department of Pathology, Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, Washington, USA; and mtchin@u.washington.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chin
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism; D006339:Heart Rate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C485778:Hey2 protein, mouse
keywords: Brugada syndrome; Notch signaling; electrophysiology; heart rate variability