This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsuji, Y. Articles by Nattel, S. Search for Related Content PubMed PubMed Citation Articles by Tsuji, Y. Articles by Nattel, S. Related Collections Animal models of human disease Arrythmias-basic studies Ion channels/membrane transport

(Circulation. 2006;113:345-355.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Potassium Channel Subunit Remodeling in Rabbits Exposed to Long-Term Bradycardia or Tachycardia

Discrete Arrhythmogenic Consequences Related to Differential Delayed-Rectifier Changes

Yukiomi Tsuji, MD; Stephen Zicha, PhD; Xiao-Yan Qi, PhD; Itsuo Kodama, MD; Stanley Nattel, MD

From the Research Center and Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada (Y.T., S.Z., X.Y.Q., S.N.); Department of Pharmacology, McGill University, Montreal, Quebec, Canada (S.Z., S.N.); and Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya City, Japan (I.K.).

Correspondence to Stanley Nattel, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail stanley.nattel{at}icm-mhi.org

Received March 30, 2005; revision received November 2, 2005; accepted November 18, 2005.

Background— Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits.

Methods and Results— We evaluated mRNA and protein expression of subunits underlying rapid (I_Kr) and slow (I_Ks) delayed-rectifier and transient-outward K⁺ currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by 50% at 60 bpm; P<0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced and tachypaced rabbits, whereas ERG was significantly downregulated in bradypaced rabbits only. Kv4.3 and Kv1.4 were downregulated by tachypacing only. Patch-clamp experiments showed that I_Ks was reduced in both but I_Kr was decreased in bradypaced rabbits only. Continuous monitoring revealed spontaneous TdP in 75% of bradypaced but only isolated ventricular ectopy in tachypaced rabbits. Administration of dofetilide (0.02 mg/kg) to mimic I_Kr downregulation produced ultimately lethal TdP in all tachypaced rabbits.

Conclusions— Sustained tachycardia and bradycardia downregulate I_Ks subunits, but bradycardia also suppresses ERG/I_Kr, causing prominent repolarization delays and spontaneous TdP. Susceptibility of tachycardia/heart failure rabbits to malignant tachyarrhythmias is induced by exposure to I_Kr blockers. These results point to a crucial role for delayed-rectifier subunit remodeling in TdP susceptibility associated with rate-related cardiac remodeling.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				X. Qi, Y.-H. Yeh, D. Chartier, L. Xiao, Y. Tsuji, B. J.J.M. Brundel, I. Kodama, and S. Nattel The Calcium/Calmodulin/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 295 - 304. [Abstract] [Full Text] [PDF]

				A. Maguy, S. Le Bouter, P. Comtois, D. Chartier, L. Villeneuve, R. Wakili, K. Nishida, and S. Nattel Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers: A Potential Role in Conduction Abnormalities Associated With Congestive Heart Failure Circ. Res., May 8, 2009; 104(9): 1113 - 1122. [Abstract] [Full Text] [PDF]

				T. Aiba, G. G. Hesketh, A. S. Barth, T. Liu, S. Daya, K. Chakir, V. L. Dimaano, T. P. Abraham, B. O'Rourke, F. G. Akar, et al. Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy Circulation, March 10, 2009; 119(9): 1220 - 1230. [Abstract] [Full Text] [PDF]

				G. Michael, L. Xiao, X.-Y. Qi, D. Dobrev, and S. Nattel Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis Cardiovasc Res, February 15, 2009; 81(3): 491 - 499. [Abstract] [Full Text] [PDF]

				S. Nattel Delayed-rectifier potassium currents and the control of cardiac repolarization: Noble and Tsien 40 years after J. Physiol., December 15, 2008; 586(24): 5849 - 5852. [Full Text] [PDF]

				L. Xiao, P. Coutu, L. R. Villeneuve, A. Tadevosyan, A. Maguy, S. Le Bouter, B. G. Allen, and S. Nattel Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes Circ. Res., September 26, 2008; 103(7): 733 - 742. [Abstract] [Full Text] [PDF]

				T. G. Diness, Y.-H. Yeh, X. Y. Qi, D. Chartier, Y. Tsuji, R. S. Hansen, S.-P. Olesen, M. Grunnet, and S. Nattel Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome Cardiovasc Res, July 1, 2008; 79(1): 61 - 69. [Abstract] [Full Text] [PDF]

				S. Nattel Effects of Heart Disease on Cardiac Ion Current Density Versus Current Amplitude: Important Conceptual Subtleties in the Language of Arrhythmogenic Ion Channel Remodeling Circ. Res., June 6, 2008; 102(11): 1298 - 1300. [Full Text] [PDF]

				K. J. Sampson, C. Terrenoire, D. O. Cervantes, R. A. Kaba, N. S. Peters, and R. S. Kass Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse J. Physiol., January 15, 2008; 586(2): 627 - 637. [Abstract] [Full Text] [PDF]

				K. Ahmad and P. Dorian Drug-induced QT prolongation and proarrhythmia: an inevitable link? Europace, September 1, 2007; 9(suppl_4): iv16 - iv22. [Abstract] [Full Text] [PDF]

				S. K.G. Winckels, M. B. Thomsen, P. Oosterhoff, A. Oros, J. D.M. Beekman, N. J.M. Attevelt, L. Kretzers, and M. A. Vos High-Septal Pacing Reduces Ventricular Electrical Remodeling and Proarrhythmia in Chronic Atrioventricular Block Dogs J. Am. Coll. Cardiol., August 28, 2007; 50(9): 906 - 913. [Abstract] [Full Text] [PDF]

				S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]

				F. Suto, W. Zhu, A. Chan, and G. J. Gross IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1782 - H1788. [Abstract] [Full Text] [PDF]

				Z. Mustapha, L. Pang, and S. Nattel Characterization of the cardiac KCNE1 gene promoter Cardiovasc Res, January 1, 2007; 73(1): 82 - 91. [Abstract] [Full Text] [PDF]

				R. J. Sung, S.-N. Wu, J.-S. Wu, H.-D. Chang, and C.-H. Luo Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2597 - H2605. [Abstract] [Full Text] [PDF]

				A. Kijtawornrat, Y. Nishijima, B. M. Roche, B. W. Keene, and R. L. Hamlin Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity Toxicol. Sci., September 1, 2006; 93(1): 205 - 212. [Abstract] [Full Text] [PDF]