title: Post-operative atrial fibrillation is associated with a pre-existing structural and electrical substrate in human right atrial myocardium.
abstract: BACKGROUND
  Post-operative atrial fibrillation (POAF) is a major health economic burden. However, the precise mechanisms in POAF remain unclear. In other forms of AF, sites of high dominant frequency (DF) in sinus rhythm (SR) may harbour 'AF nests'. We studied AF inducibility in relation to substrate changes using epicardial electrograms and cardiomyocyte calcium handling in the atria of AF naïve patients.
  
  
  METHODS
  Bipolar electrograms were recorded from the lateral right atrial (RA) wall in 34 patients undergoing coronary surgery using a high-density array in sinus rhythm (NSR). RA burst pacing at 200/500/1000ms cycle lengths (CL) was performed, recording episodes of AF>30s. Co-localised RA tissue was snap frozen for RNA and protein extraction.
  
  
  RESULTS
  Electrograms prolonged during AF (76.64±29.35ms) vs. NSR/pacing (p<0.001). Compared to NSR, electrogram amplitude was reduced during AF and during pacing at 200ms CL (p<0.001). Electrogram DF was significantly lower in AF (75.87±23.63Hz) vs. NSR (89.33±25.99Hz) (p<0.05), and NSR DF higher in AF inducible patients at the site of AF initiation (p<0.05). Structurally, POAF atrial myocardium demonstrated reduced sarcolipin gene (p=0.0080) and protein (p=0.0242) expression vs. NSR. Phospholamban gene and protein expression was unchanged. SERCA2a protein expression remained unchanged, but MYH6 (p=0.0297) and SERCA2A (p=0.0343) gene expression was reduced in POAF.
  
  
  CONCLUSIONS
  Human atrial electrograms prolong and reduce in amplitude in induced peri-operative AF vs. NSR or pacing. In those sustaining AF, high DF sites in NSR may indicate 'AF nests'. This electrical remodelling is accompanied by structural remodelling with altered expression of cardiomyocyte calcium handling detectable before POAF. These novel upstream substrate changes offer a novel mechanism and manifestation of human POAF.
authors.affiliation: Myocardial Function, National Heart & Lung Institute, Hammersmith Hospital, Imperial College London, UK; Cardiovascular Medicine, Stanford University, Palo Alto, USA.
authors.forename: Junaid A B
authors.initials: JA
authors.lastname: Zaman
authors.affiliation: Myocardial Function, National Heart & Lung Institute, Hammersmith Hospital, Imperial College London, UK; Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, UK; Department of Biomolecular Medicine, South Kensington Campus, Imperial College London, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Harling
authors.affiliation: Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, UK; Department of Biomolecular Medicine, South Kensington Campus, Imperial College London, UK.
authors.forename: Hutan
authors.initials: H
authors.lastname: Ashrafian
authors.affiliation: Myocardial Function, National Heart & Lung Institute, Hammersmith Hospital, Imperial College London, UK.
authors.forename: Ara
authors.initials: A
authors.lastname: Darzi
authors.affiliation: Department of Biomolecular Medicine, South Kensington Campus, Imperial College London, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Gooderham
authors.affiliation: Myocardial Function, National Heart & Lung Institute, Hammersmith Hospital, Imperial College London, UK; Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, UK. Electronic address: t.athansiou@imperial.ac.uk.
authors.forename: Thanos
authors.initials: T
authors.lastname: Athanasiou
authors.affiliation: Myocardial Function, National Heart & Lung Institute, Hammersmith Hospital, Imperial College London, UK.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Peters
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000175:diagnosis* / Q000503:physiopathology*; D016280:Atrial Function, Right / Q000502:physiology; D015331:Cohort Studies; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods*; D005260:Female; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000175:diagnosis* / Q000503:physiopathology*; D011446:Prospective Studies
keywords: Atrial fibrillation; Calcium handling; Dominant frequency; Electrograms; Post-operative