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© 1997 American Heart Association, Inc.
Articles |
Outward K+ Current Densities and Kv1.5 Expression Are Reduced in Chronic Human Atrial Fibrillation
From the Departments of Cardiology (D.R. Van W.) and Cardiothoracic Surgery (P.M.M.), The Cleveland (Ohio) Clinic Foundation; the Department of Molecular Biology and Pharmacology (A.L.P., J.M.N.), Washington University School of Medicine, St Louis, Mo; and the Department of Biochemistry and Cell Biology (J.S.T.), State University of New York at Stony Brook.
Correspondence to Jeanne M. Nerbonne, PhD, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail jnerbonn{at}pharmdec.wustl.edu
Abstract Chronic atrial fibrillation is associated with a
shortening of the atrial action potential duration and atrial
refractory period. To test the hypothesis that these changes are
mediated by changes in the density of specific atrial K+
currents, we compared the density of K+ currents in left
and right atrial myocytes and the density of delayed rectifier
K+ channel 
-subunit proteins (Kv1.5 and Kv2.1) in left
and right atrial appendages from patients (n=28) in normal sinus rhythm
with those from patients (n=15) in chronic atrial fibrillation (AF).
Contrary to our expectations, nystatin–perforated patch
recordings of whole-cell K+ currents revealed
significant reductions in both the inactivating
(ITO) and sustained
(IKsus) outward K+ current densities
in left and right atrial myocytes isolated from patients in chronic AF,
relative to the ITO and
IKsus densities in myocytes isolated from
patients in normal sinus rhythm. Quantitative Western blot
analysis revealed that although there was no change in the
expression of the Kv2.1 protein, the expression of Kv1.5 protein was
reduced by >50% in both the left and the right atrial appendages of
AF patients. The finding that Kv1.5 expression is reduced in parallel
with the reduction in delayed rectifier K+ current density
is consistent with recent suggestions that Kv1.5 underlies the
major component of the delayed rectifier K+ current in
human atrial myocytes, the ultrarapid delayed rectifier K+
current, IKur. The unexpected finding of reduced
voltage-gated outward K+ current densities in atrial
myocytes from AF patients demonstrates the need to further examine the
details of the electrophysiological
remodeling that occurs during AF to enable more effective and safer
therapeutic strategies to be developed.
Key Words: K+ channels • atrial fibrillation • Kv1.5 • Kv2.1 • action potential duration
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V. L.J.L. Thijssen, J. Ausma, and M. Borgers Structural remodelling during chronic atrial fibrillation: act of programmed cell survival Cardiovasc Res, October 1, 2001; 52(1): 14 - 24. [Abstract] [Full Text] [PDF]
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C. A. Carnes, M. K. Chung, T. Nakayama, H. Nakayama, R. S. Baliga, S. Piao, A. Kanderian, S. Pavia, R. L. Hamlin, P. M. McCarthy, et al. Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation Circ. Res., September 14, 2001; 89 (6): e32 - e38. [Abstract] [Full Text] [PDF]
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L. Polontchouk, J.-A. Haefliger, B. Ebelt, T. Schaefer, D. Stuhlmann, U. Mehlhorn, F. Kuhn-Regnier, E. R. De Vivie, and S. Dhein Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria J. Am. Coll. Cardiol., September 1, 2001; 38(3): 883 - 891. [Abstract] [Full Text] [PDF]
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 E. BERTAGLIA, D. D'ESTE, A. ZANOCCO, F. ZERBO, and P. PASCOTTO Effects of pretreatment with verapamil on early recurrences after electrical cardioversion of persistent atrial fibrillation: a randomised study Heart, May 1, 2001; 85(5): 578 - 580. [Full Text]
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T. González, M. Longobardo, R. Caballero, E. Delpón, J. Tamargo, and C. Valenzuela Effects of Bupivacaine and a Novel Local Anesthetic, IQB-9302, on Human Cardiac K+ Channels J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 573 - 583. [Abstract] [Full Text]
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C Pandozi and M Santini Update on atrial remodelling owing to rate. Does atrial fibrillation always 'beget' atrial fibrillation? Eur. Heart J., April 1, 2001; 22(7): 541 - 553. [PDF]
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M. A. Allessie, P. A. Boyden, A. J. Camm, A. G. Kleber, M. J. Lab, M. J. Legato, M. R. Rosen, P. J. Schwartz, P. M. Spooner, D. R. Van Wagoner, et al. Pathophysiology and Prevention of Atrial Fibrillation Circulation, February 6, 2001; 103(5): 769 - 777. [Full Text] [PDF]
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C. Pandozi, L. Bianconi, L. Calo, A. Castro, F. Lamberti, M. C. Scianaro, G. Gentilucci, and M. Santini Postcardioversion atrial electrophysiologic changes induced by oral verapamil in patients with persistent atrial fibrillation J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2234 - 2241. [Abstract] [Full Text] [PDF]
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 C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]
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Y.-G. Wang, M. B. Wagner, R. Kumar, W. N. Goolsby, and R. W. Joyner Fast pacing facilitates discontinuous action potential propagation between rabbit atrial cells Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2095 - H2103. [Abstract] [Full Text] [PDF]
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L. Yue, Z. Wang, H. Rindt, and S. Nattel Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium J. Physiol., September 15, 2000; 527(3): 467 - 478. [Abstract] [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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D. Dobrev, E. Wettwer, H. M. Himmel, A. Kortner, E. Kuhlisch, S. Schuler, W. Siffert, and U. Ravens G-Protein {beta}3-Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents Circulation, August 8, 2000; 102(6): 692 - 697. [Abstract] [Full Text] [PDF]
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D. Li, P. Melnyk, J. Feng, Z. Wang, K. Petrecca, A. Shrier, and S. Nattel Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology Circulation, June 6, 2000; 101(22): 2631 - 2638. [Abstract] [Full Text] [PDF]
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J. M Nerbonne Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium J. Physiol., June 1, 2000; 525(2): 285 - 298. [Abstract] [Full Text] [PDF]
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T. Yamashita, Y. Murakawa, N. Hayami, E.-i. Fukui, Y. Kasaoka, M. Inoue, and M. Omata Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium : Electrical Remodeling in Paroxysmal Atrial Tachycardia Circulation, April 25, 2000; 101(16): 2007 - 2014. [Abstract] [Full Text] [PDF]
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S. K. Doshi and B. N. Singh Reviews: Pure Class III Antiarrhythmic Drugs: Focus on Dofetilide Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 237 - 247. [PDF]
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W. Guo, H. Xu, B. London, and J. M Nerbonne Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes J. Physiol., December 15, 1999; 521(3): 587 - 599. [Abstract] [Full Text] [PDF]
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S. Tessier, P. Karczewski, E.-G. Krause, Y. Pansard, C. Acar, M. Lang-Lazdunski, J.-J. Mercadier, and S. N. Hatem Regulation of the Transient Outward K+ Current by Ca2+/Calmodulin-Dependent Protein Kinases II in Human Atrial Myocytes Circ. Res., October 29, 1999; 85(9): 810 - 819. [Abstract] [Full Text] [PDF]
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H. Xu, D. M. Barry, H. Li, S. Brunet, W. Guo, and J. M. Nerbonne Attenuation of the Slow Component of Delayed Rectification, Action Potential Prolongation, and Triggered Activity in Mice Expressing a Dominant-Negative Kv2 {alpha} Subunit Circ. Res., October 1, 1999; 85(7): 623 - 633. [Abstract] [Full Text] [PDF]
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R. F. Bosch, X. Zeng, J. B. Grammer, K. Popovic, C. Mewis, and V. Kuhlkamp Ionic mechanisms of electrical remodeling in human atrial fibrillation Cardiovasc Res, October 1, 1999; 44(1): 121 - 131. [Abstract] [Full Text] [PDF]
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D. R. Van Wagoner, A. L. Pond, M. Lamorgese, S. S. Rossie, P. M. McCarthy, and J. M. Nerbonne Atrial L-Type Ca2+ Currents and Human Atrial Fibrillation Circ. Res., September 3, 1999; 85(5): 428 - 436. [Abstract] [Full Text] [PDF]
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S. Nattel Ionic Determinants of Atrial Fibrillation and Ca2+ Channel Abnormalities : Cause, Consequence, or Innocent Bystander? Circ. Res., September 3, 1999; 85(5): 473 - 476. [Full Text] [PDF]
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H. Xu, H. Li, and J. M Nerbonne Elimination of the transient outward current and action potential prolongation in mouse atrial myocytes expressing a dominant negative Kv4 {alpha} subunit J. Physiol., August 15, 1999; 519(1): 11 - 21. [Abstract] [Full Text] [PDF]
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