title: A Regional Reduction in Ito and IKACh in the Murine Posterior Left Atrial Myocardium Is Associated with Action Potential Prolongation and Increased Ectopic Activity.
abstract: The left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.
  
  
  
  We used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.
  
  
  
  Spontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.
  
  
  
  The murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Holmes
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.|Physical Sciences of Imaging in the Biomedical Sciences, School of Chemistry, College of Engineering Physical Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ting Y
authors.initials: TY
authors.lastname: Yu
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Tull
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Fahima
authors.initials: F
authors.lastname: Syeda
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kuhlmann
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Sian-Marie
authors.initials: SM
authors.lastname: O'Brien
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Patel
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Brain
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Davor
authors.initials: D
authors.lastname: Pavlovic
authors.affiliation: St George's, University of London, London, United Kingdom.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.|Department of Cardiovascular Medicine, Hospital of the University of Münster, Münster, Germany.|University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.affiliation: Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom.|Department of Cardiovascular Medicine, Hospital of the University of Münster, Münster, Germany.|University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.|Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D016275:Atrial Function / Q000502:physiology; D018880:Atrial Premature Complexes / Q000503:physiopathology*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000032:analysis / Q000502:physiology; D006325:Heart Atria / Q000737:chemistry / Q000503:physiopathology*; D007473:Ion Channels / Q000032:analysis / Q000502:physiology*; D051665:Kv1.4 Potassium Channel / Q000032:analysis / Q000502:physiology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000502:physiology; D018408:Patch-Clamp Techniques
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007473:Ion Channels; C496978:Kcna4 protein, mouse; C497067:Kcnj3 protein, mouse; C484273:Kcnj5 protein, mouse; D051665:Kv1.4 Potassium Channel