title: Fractionation of electrograms is caused by colocalized conduction block and connexin disorganization in the absence of fibrosis as AF becomes persistent in the goat model.
abstract: BACKGROUND
  Electrogram fractionation and atrial fibrosis are both thought to be pathophysiological hallmarks of evolving persistence of atrial fibrillation (AF), but recent studies in humans have shown that they do not colocalize. The interrelationship and relative roles of fractionation and fibrotic change in AF persistence therefore remain unclear.
  
  
  OBJECTIVE
  The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing or block due to changes in atrial connexin distribution in the absence of fibrotic change.
  
  
  METHODS
  Of 12 goats, atrial burst pacemakers maintained AF in 9 goats for up to 3 consecutive 4-week periods. After each 4-week period, 3 goats underwent epicardial mapping studies of the right atrium and examination of the atrial myocardium for immunodetection of connexins 43 and 40 (Cx43 and Cx40) and quantification of connective tissue.
  
  
  RESULTS
  Despite refractoriness returning to normal in between each 4-week period of AF, there was a cumulative increase in the prevalence of fractionated atrial electrograms during both atrial pacing (control and 1, 2, and 3 months period of AF 0.3%, 1.3% ± 1.5%, 10.6% ± 2%, and 17% ± 5%, respectively; analysis of variance, P < .05) and AF (0.3% ± 0.1%, 2.3% ± 1.2%, 14% ± 2%, and 23% ± 3%; P < .05) caused by colocalized areas of conduction block during both pacing (local conduction velocity <10 cm/s: 0.1% ± 0.1%, 0.3% ± 0.6%, 6.5% ± 3%, and 6.9% ± 4%; P < .05) and AF (1.5% ± 0.5%, 2.7% ± 1.1%, 10.1% ± 1.2%, and 13.6% ± 0.4%; P < .05), associated with an increase in the heterogeneity of Cx40 and lateralization of Cx43 (lateralization scores: 1.75 ± 0.89, 1.44 ± 0.31, 2.85 ± 0.96, and 2.94 ± 0.31; P < .02), but not associated with change in connective tissue content or net conduction velocity.
  
  
  CONCLUSIONS
  Electrogram fractionation with increasing persistence of AF results from slow localized conduction or block associated with changes in atrial connexin distribution in the absence of fibrotic change.
authors.affiliation: Manchester Heart Centre, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom. Electronic address: senthilk1uk@yahoo.co.uk.
authors.forename: Senthil
authors.initials: S
authors.lastname: Kirubakaran
authors.affiliation: Imperial College London, London, SW7 2AZ, United Kingdom.
authors.forename: Rasheda A
authors.initials: RA
authors.lastname: Chowdhury
authors.affiliation: Manchester Heart Centre, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.
authors.forename: Mark C S
authors.initials: MC
authors.lastname: Hall
authors.affiliation: Imperial College London, London, SW7 2AZ, United Kingdom.
authors.forename: Pravina M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: Manchester Heart Centre, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Garratt
authors.affiliation: Imperial College London, London, SW7 2AZ, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Peters
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology*; D017630:Connexins / Q000378:metabolism*; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005355:Fibrosis; D006041:Goats; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology*; D006327:Heart Block / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology*; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D019028:Magnetic Resonance Imaging, Cine; D011379:Prognosis
chemical_list: D017630:Connexins
keywords: Atrial fibrillation; Conduction; Connexin; Fractionation