title: Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization.
abstract: OBJECTIVE
  Mice with cardiac-specific overexpression of human angiotensin II type 1 receptor (AT1R) undergo cardiac remodelling and die prematurely of sudden death. Since excessive QT prolongation is a major risk factor for ventricular arrhythmias and sudden death, we hypothesize that chronic stimulation of AT1R might contribute to sudden death by promoting delayed repolarization and ventricular arrhythmias.
  
  
  METHODS
  In the present study, a detailed analysis of ventricular repolarization parameters was undertaken in AT1R mice.
  
  
  RESULTS
  Measurement of K+ currents in ventricular myocytes isolated from 6-8 months AT1R male mice revealed a significant reduction of the Ca2+-independent transient outward (I(to)), the ultra-rapid delayed rectifier (I Kur)), and the inward rectifier (I K1) K+ currents compared with littermate controls (CTL). The expression of the underlying K+ channels was also decreased in AT1R ventricles. Moreover, reactivation of I(to) was slower in AT1R mice. Consistent with these findings, AT1R mice presented a longer action potential duration (APD90, CTL: 19.0 +/- 1.8 ms; AT1R: 39.1 +/- 4.7 ms, P = 0.0001) and QTc interval (CTL: 53.6 +/- 1.5 ms, AT1R: 64.2 +/- 1.4 ms, P = 0.0005). In addition, spontaneous ventricular arrhythmias were reported in the AT1R mice. Importantly, the increased incidence of arrhythmia and the repolarization defects also occurred in much younger AT1R mice that do not present signs of hypertrophy, confirming that these arrhythmogenic changes are not secondary to cardiac remodelling.
  
  
  CONCLUSIONS
  These results strongly suggest that chronic stimulation of AT1R directly leads to an increased incidence of cardiac arrhythmia associated with delayed repolarization.
authors.affiliation: Research Centre, Montreal Heart Institute, 5000 Rue Bélanger, Montréal, QC, Canada H1T 1C8.
authors.forename: Katy
authors.initials: K
authors.lastname: Rivard
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Céline
authors.initials: C
authors.lastname: Fiset
mesh_terms: D000200:Action Potentials; D000367:Age Factors; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism; D004562:Electrocardiography; D006329:Heart Conduction System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D051668:Delayed Rectifier Potassium Channels; D044140:Receptor, Angiotensin, Type 1; D011188:Potassium