Cardiovascular Research Advance Access originally published online on January 31, 2008
Cardiovascular Research 2008 78(1):53-62; doi:10.1093/cvr/cvn020
Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization
1 Research Centre, Montreal Heart Institute, 5000 Rue Bélanger, Montréal, QC, Canada H1T 1C8
2 Université de Montréal, Faculty of Pharmacy, Montréal, QC, Canada
3 Institut de Recherche Clinique de Montréal, Montréal, QC, Canada
*Corresponding author. Tel: + 1 514 376 3330 (3025); fax: + 1 514 376 1355. E-mail address: celine.fiset{at}icm-mhi.org
Aims: 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 (Ito), the ultra-rapid delayed rectifier (IKur), and the inward rectifier (IK1) K+ currents compared with littermate controls (CTL). The expression of the underlying K+ channels was also decreased in AT1R ventricles. Moreover, reactivation of Ito 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.
Conclusion: These results strongly suggest that chronic stimulation of AT1R directly leads to an increased incidence of cardiac arrhythmia associated with delayed repolarization.
KEYWORDS Angiotensin II; K+ currents; Ventricular repolarization; Arrhythmias; Transgenic mice
Time for primary review: 41 days
Present address: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Rivard, V. Trepanier-Boulay, H. Rindt, and C. Fiset Electrical remodeling in a transgenic mouse model of {alpha}1B-adrenergic receptor overexpression Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H704 - H718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F.X. Ainscough, M. J. Drinkhill, A. Sedo, N. A. Turner, D. A. Brooke, A. J. Balmforth, and S. G. Ball Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction Cardiovasc Res, February 15, 2009; 81(3): 592 - 600. [Abstract] [Full Text] [PDF]
|
|