title: LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation.
abstract: OBJECTIVE
  Liver kinase B1 (LKB1) is a protein kinase that activates the metabolic regulator AMP-activated protein kinase (AMPK) and other related kinases. Deletion of LKB1 in mice leads to cardiomyopathy and atrial fibrillation (AF). However, the specific role of the LKB1 pathway in early atrial biology remains unknown. Thus, we investigated whether LKB1 deletion altered atrial channel expression and electrophysiological function in a cardiomyocyte-specific knockout mouse model.
  
  
  RESULTS
  We performed a systematic comparison of αMHC-Cre LKB1(fl/fl) and littermate LKB1(fl/fl) male mice. This included analysis of gene expression, histology, and echocardiography, as well as cellular and tissue-level electrophysiology using patch-clamp recordings in vitro, optical mapping ex vivo, and ECG recordings in vivo. At postnatal day 1, atrial depolarization was prolonged, and Nav1.5 and Cx40 expression were markedly down-regulated in MHC-Cre LKB1(fl/fl) mice. Inward sodium current density was significantly decreased in MHC-Cre LKB1(fl/fl) neonatal atrial myocytes. Subsequently, additional alterations in atrial channel expression, atrial fibrosis, and spontaneous onset of AF developed by 2 weeks of age. In adult mice, abnormalities of interatrial conduction and bi-atrial electrical coupling were observed, likely promoting the perpetuation of AF. Mice with AMPK-inactivated hearts demonstrated modest overlap in channel expression with MHC-Cre LKB1(fl/fl) hearts, but retained normal structure, electrophysiological function and contractility.
  
  
  CONCLUSIONS
  Deletion of LKB1 causes early defects in atrial channel expression, action potential generation and conduction, which precede widespread atrial remodelling, fibrosis and AF. LKB1 is critical for normal atrial growth and electrophysiological function.
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Ross
authors.affiliation: Cardiovascular Research Center, Mt. Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Chaoqin
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Su
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Palmeri
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ashraf
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Akar
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.affiliation: Cardiovascular Research Center, Mt. Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Akar
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA lawrence.young@yale.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000503:physiopathology; D017630:Connexins / Q000032:analysis; D006325:Heart Atria / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000097003:Gap Junction alpha-5 Protein
chemical_list: D055372:AMP-Activated Protein Kinases; D017630:Connexins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017346:Protein Serine-Threonine Kinases; D000097003:Gap Junction alpha-5 Protein; C568321:Scn5a protein, mouse; C491654:Stk11 protein, mouse
keywords: Atrial fibrillation; Cellular signalling pathways; LKB1