© 1999 American Heart Association, Inc.
Original Contribution |
Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation
From the Department of Pharmacology and Therapeutics (L.Y., S.N.) and the Department of Pathology (P.M.), McGill University; the Department of Medicine (R.G., Z.W., S.N.), University of Montreal; and the Research Center (L.Y., P.M., R.G., Z.W., S.N.), Montreal Heart Institute, Montreal, Quebec, Canada.
Correspondence to Stanley Nattel, MD, Research Center, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec, H1T 1C8, Canada. E-mail nattel{at}icm.umontreal.ca
Abstract—The rapid atrial rate
during atrial fibrillation (AF) decreases the ionic current density of
transient outward K+ current, L-type Ca2+
current, and Na+ current, thereby altering cardiac
electrophysiology and promoting arrhythmia maintenance.
To assess possible underlying changes in cardiac gene expression, we
applied competitive reverse transcriptase–polymerase chain reaction to
quantify mRNA concentrations in dogs subjected to 7 (group P7 dogs) or
42 (group P42 dogs) days of atrial pacing at 400 bpm and in sham
controls. Rapid pacing reduced mRNA concentrations of Kv4.3 (putative
gene encoding transient outward K+ current; by 60% in P7
and 74% in P42 dogs; P<0.01 and
P<0.001, respectively, versus shams), the
1c subunit of L-type Ca2+ channels (by 57%
in P7 and 72% in P42 dogs; P<0.01 versus shams for
each) and the subunit of cardiac Na+ channels (by 18%
in P7 and 42% in P42; P=NS and P<0.01,
respectively, versus shams) genes. The observed changes in ion channel
mRNA concentrations paralleled previously measured changes in
corresponding atrial ionic current densities. Atrial
tachycardia did not affect mRNA concentrations of genes
encoding delayed or Kir2.1 inward rectifier K+ currents (of
which the densities are unchanged by atrial tachycardia) or
of the Na+,Ca2+ exchanger. Western blot
techniques were used to quantify protein expression for Kv4.3 and
Na+ channel subunits, which were decreased by 72% and
47%, respectively, in P42 dogs (P<0.001 versus control
for each), in a manner quantitatively similar to measured changes in
mRNA and currents, whereas Na+,Ca2+ exchanger
protein concentration was unchanged. We conclude that chronic atrial
tachycardia alters atrial ion channel gene expression,
thereby altering ionic currents in a fashion that promotes the
occurrence of AF. These observations provide a potential molecular
basis for the self-perpetuating nature of AF.
Key Words: arrhythmia, cardiac • molecular biology • channels, ion • remodeling, atrial • Ca2+ • K+
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H. M.W. van der Velden, J. Ausma, M. B. Rook, A. J.C.G.M. Hellemons, T. A.A.B. van Veen, M. A. Allessie, and H. J. Jongsma Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat Cardiovasc Res, June 1, 2000; 46(3): 476 - 486. [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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G. U. Ahmmed, P. H. Dong, G. Song, N. A. Ball, Y. Xu, R. A. Walsh, and N. Chiamvimonvat Changes in Ca2+ Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure Circ. Res., March 17, 2000; 86(5): 558 - 570. [Abstract] [Full Text] [PDF]
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S. Nattel, C. Matthews, E. De Blasio, W. Han, D. Li, and L. Yue Dose-Dependence of 4-Aminopyridine Plasma Concentrations and Electrophysiological Effects in Dogs : Potential Relevance to Ionic Mechanisms In Vivo Circulation, March 14, 2000; 101(10): 1179 - 1184. [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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C. Boixel, W. Gonzalez, L. Louedec, and S. N. Hatem Mechanisms of L-Type Ca2+ Current Downregulation in Rat Atrial Myocytes During Heart Failure Circ. Res., September 28, 2001; 89(7): 607 - 613. [Abstract] [Full Text] [PDF]
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