Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation

Author:

Yue Lixia1,Melnyk Peter1,Gaspo Rania1,Wang Zhiguo1,Nattel Stanley1

Affiliation:

1. 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.

Abstract

Abstract —The rapid atrial rate during atrial fibrillation (AF) decreases the ionic current density of transient outward K + current, L-type Ca 2+ 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 α 1c subunit of L-type Ca 2+ channels (by 57% in P7 and 72% in P42 dogs; P <0.01 versus shams for each) and the α 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 + ,Ca 2+ exchanger. Western blot techniques were used to quantify protein expression for Kv4.3 and Na + channel α 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 + ,Ca 2+ 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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