title: Cardiac Rac1 overexpression in mice creates a substrate for atrial arrhythmias characterized by structural remodelling.
abstract: OBJECTIVE
  The small GTPase Rac1 seems to play a role in the pathogenesis of atrial fibrillation (AF). The aim of the present study was to characterize the effects of Rac1 overexpression on atrial electrophysiology.
  
  
  RESULTS
  In mice with cardiac overexpression of constitutively active Rac1 (RacET), statin-treated RacET, and wild-type controls (age 6 months), conduction in the right and left atrium (RA and LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined and inducibility of atrial arrhythmias was tested. Action potentials were recorded in isolated cells. Left ventricular function was measured by pressure-volume analysis. Five of 11 RacET hearts showed spontaneous or inducible atrial tachyarrhythmias vs. 0 of 9 controls (P < 0.05). In RacET, the P-wave duration was significantly longer (26.8 +/- 2.1 vs. 16.7 +/- 1.1 ms, P = 0.001) as was total atrial activation time (RA: 13.6 +/- 4.4 vs. 3.2 +/- 0.5 ms; LA: 7.1 +/- 1.2 vs. 2.2 +/- 0.3 ms, P < 0.01). Prolonged local conduction times occurred more often in RacET (RA: 24.4 +/- 3.8 vs. 2.7 +/- 2.1%; LA: 19.1 +/- 6.3 vs. 1.2 +/- 0.7%, P < 0.01). The AERP and action potential duration did not differ significantly between both groups. RacET demonstrated significant atrial fibrosis but only moderate systolic heart failure. RacET and statin-treated RacET were not significantly different regarding atrial electrophysiology.
  
  
  CONCLUSIONS
  The substrate for atrial arrhythmias in mice with Rac1 overexpression is characterized by conduction disturbances and atrial fibrosis. Electrical remodelling (i.e. a shortening of AERP) does not play a role. Statin treatment cannot prevent the structural and electrophysiological effects of pronounced Rac1 overexpression in this model.
authors.affiliation: Klinik für Innere Medizin III (Kardiologie, Angiologie, Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Kirrberger Strasse, Homburg/Saar D 66421, Germany. reil@med-in.uni-saarland.de
authors.forename: Jan-Christian
authors.initials: JC
authors.lastname: Reil
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.forename: Martin
authors.initials: M
authors.lastname: Oberhofer
authors.forename: Andrey
authors.initials: A
authors.lastname: Kazakov
authors.forename: Lars
authors.initials: L
authors.lastname: Kaestner
authors.forename: Patrick
authors.initials: P
authors.lastname: Mueller
authors.forename: Oliver
authors.initials: O
authors.lastname: Adam
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Christian
authors.initials: C
authors.lastname: Mewis
authors.forename: Maurits
authors.initials: M
authors.lastname: Allessie
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Hans-Ruprecht
authors.initials: HR
authors.lastname: Neuberger
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects; D004562:Electrocardiography; D005355:Fibrosis; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020830:rac1 GTP-Binding Protein