title: LKB1 knockout mouse develops spontaneous atrial fibrillation and provides mechanistic insights into human disease process.
abstract: BACKGROUND
  Atrial fibrillation (AF) is a complex disease process, and the molecular mechanisms underlying initiation and progression of the disease are unclear. Consequently, AF has been difficult to model. In this study, we have presented a novel transgenic mouse model of AF that mimics human disease and characterized the mechanisms of atrial electroanatomical remodeling in the genesis of AF.
  
  
  RESULTS
  Cardiac-specific liver kinase B1 (LKB1) knockout (KO) mice were generated, and 47% aged 4 weeks and 95% aged 12 weeks developed spontaneous AF from sinus rhythm by demonstrating paroxysmal and persistent stages of the disease. Electrocardiographic characteristics of sinus rhythm were similar in KO and wild-type mice. Atrioventricular block and atrial flutter were common in KO mice. Heart rate was slower with persistent AF. In parallel with AF, KO mice developed progressive biatrial enlargement with inflammation, heterogeneous fibrosis, and loss of cardiomyocyte population with apoptosis and necrosis. Atrial tissue was infiltrated with inflammatory cells. C-reactive protein, interleukin 6, and tumor necrosis factor α were significantly elevated in serum. KO atria demonstrated elevated reactive oxygen species and decreased AMP-activated protein kinase activity. Cardiomyocyte and myofibrillar ultrastructure were disrupted. Intercellular matrix and gap junction were interrupted. Connexins 40 and 43 were reduced. Persistent AF caused left ventricular dysfunction and heart failure. Survival and exercise capacity were worse in KO mice.
  
  
  CONCLUSIONS
  LKB1 KO mice develop spontaneous AF from sinus rhythm and progress into persistent AF by replicating the human AF disease process. Progressive inflammatory atrial cardiomyopathy is the genesis of AF, through mechanistic electrical and structural remodeling.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.) Section of Cardiology, Department of Medicine, University of Chicago, IL (C.O.).
authors.forename: Cevher
authors.initials: C
authors.lastname: Ozcan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.).
authors.forename: Emily
authors.initials: E
authors.lastname: Battaglia
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.).
authors.forename: Rebeccah
authors.initials: R
authors.lastname: Young
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.).
authors.forename: Gen
authors.initials: G
authors.lastname: Suzuki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001282:Atrial Flutter / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D054537:Atrioventricular Block / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D018450:Disease Progression; D017079:Exercise Tolerance; D005355:Fibrosis; D005838:Genotype; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left; D000097003:Gap Junction alpha-5 Protein
chemical_list: D055372:AMP-Activated Protein Kinases; D018031:Connexin 43; D017630:Connexins; D018836:Inflammation Mediators; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000097003:Gap Junction alpha-5 Protein; C543076:GJA1 protein, mouse; C491654:Stk11 protein, mouse
keywords: animal models of human disease remodeling; atrial fibrillation; atrium; inflammation; pathogenesis