title: Total beta-adrenoceptor knockout slows conduction and reduces inducible arrhythmias in the mouse heart.
abstract: BACKGROUND
  Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β(1), β(2), β(3)) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.
  
  
  METHODS
  In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.
  
  
  RESULTS
  The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.
  
  
  CONCLUSIONS
  TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target.
authors.affiliation: Department of Medicine-Cardiology, University Hospital of Bonn, Bonn, Germany. florian.stoeckigt@ukb.uni-bonn.de
authors.forename: Florian
authors.initials: F
authors.lastname: Stöckigt
authors.forename: Klara
authors.initials: K
authors.lastname: Brixius
authors.forename: Lars
authors.initials: L
authors.lastname: Lickfett
authors.forename: René
authors.initials: R
authors.lastname: Andrié
authors.forename: Markus
authors.initials: M
authors.lastname: Linhart
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Jan Wilko
authors.initials: JW
authors.lastname: Schrickel
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology* / Q000628:therapy; D001281:Atrial Fibrillation / Q000235:genetics; D004562:Electrocardiography / Q000379:methods; D055724:Electrophysiological Phenomena; D004594:Electrophysiology; D006325:Heart Atria / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology; D006339:Heart Rate; D051379:Mice; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics
chemical_list: D011943:Receptors, Adrenergic, beta