title: Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-β1.
abstract: BACKGROUND
  Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1).
  
  
  RESULTS
  MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a.
  
  
  CONCLUSIONS
  Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Eue-Keun
authors.initials: EK
authors.lastname: Choi
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart-von der Lohe
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016275:Atrial Function / Q000187:drug effects; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D012433:Ryanodine / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; D012433:Ryanodine; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse