title: Overexpression of cAMP-response element modulator causes abnormal growth and development of the atrial myocardium resulting in a substrate for sustained atrial fibrillation in mice.
abstract: METHODS
  Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. The substrate of AF is composed of a complex interplay between structural and functional changes of the atrial myocardium often preceding the occurrence of persistent AF. However, there are only few animal models reproducing the slow progression of the AF substrate to the spontaneous occurrence of the arrhythmia. Transgenic mice (TG) with cardiomyocyte-directed expression of CREM-IbΔC-X, an isoform of transcription factor CREM, develop atrial dilatation and spontaneous-onset AF. Here we tested the hypothesis that TG mice develop an arrhythmogenic substrate preceding AF using physiological and biochemical techniques.
  
  
  RESULTS
  Overexpression of CREM-IbΔC-X in young TG mice (<8weeks) led to atrial dilatation combined with distension of myocardium, elongated myocytes, little fibrosis, down-regulation of connexin 40, loss of excitability with a number of depolarized myocytes, atrial ectopies and inducibility of AF. These abnormalities continuously progressed with age resulting in interatrial conduction block, increased atrial conduction heterogeneity, leaky sarcoplasmic reticulum calcium stores and the spontaneous occurrence of paroxysmal and later persistent AF. This distinct atrial remodelling was associated with a pattern of non-regulated and up-regulated marker genes of myocardial hypertrophy and fibrosis.
  
  
  CONCLUSIONS
  Expression of CREM-IbΔC-X in TG hearts evokes abnormal growth and development of the atria preceding conduction abnormalities and altered calcium homeostasis and the development of spontaneous and persistent AF. We conclude that transcription factor CREM is an important regulator of atrial growth implicated in the development of an arrhythmogenic substrate in TG mice.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Münster, Germany.
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Eloi
authors.initials: E
authors.lastname: Marijon
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.forename: Kirsten
authors.initials: K
authors.lastname: Schulte
authors.forename: Juliane
authors.initials: J
authors.lastname: Hanstein
authors.forename: Jan S
authors.initials: JS
authors.lastname: Schulte
authors.forename: Mathis
authors.initials: M
authors.lastname: Vogel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.forename: Sandra
authors.initials: S
authors.lastname: Laakmann
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmueller
authors.forename: Jens
authors.initials: J
authors.lastname: Eckstein
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.forename: Sven
authors.initials: S
authors.lastname: Kaese
authors.forename: Ariane
authors.initials: A
authors.lastname: Staab
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grote-Wessels
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Ghassan
authors.initials: G
authors.lastname: Moubarak
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hatem
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Müller
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D013997:Time Factors
chemical_list: C497411:Crem protein, mouse; D051786:Cyclic AMP Response Element Modulator
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