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EXPERIMENTAL STUDY

Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I_Ca,L and I_to in rapid atrial pacing in rabbits

Ralph F. Bosch, MD^*,*, Constanze R. Scherer, PhD, Norman Rüb, MD^*, Stefan Wöhrl, MSc^*, Klaus Steinmeyer, PhD, Hannelore Haase, PhD, Andreas E. Busch, PhD, Ludger Seipel, MD^* and Volker Kühlkamp, MD^*

^* Department of Cardiology, University of Tübingen, Tübingen, Germany
Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt, Germany
Max-Delbrück Center for Molecular Medicine, Berlin, Germany

Manuscript received April 9, 2002; revised manuscript received August 10, 2002, accepted September 6, 2002.

^* Reprint requests and correspondence: Dr. Ralph F. Bosch, Dept. of Cardiology, University of Tuebingen, Otfried-Mueller-Str. 10, D-72076 Tuebingen, Germany.
ralph.bosch{at}uni-tuebingen.de

OBJECTIVES: The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP).

BACKGROUND: Long-term atrial fibrillation reduces L-type Ca²⁺ (I_Ca,L) and transient outward K⁺ (I_to) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown.

METHODS: Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively.

RESULTS: L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca²⁺ channel ß subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the ₁ subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I_to. Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected.

CONCLUSIONS: L-type calcium current and I_to are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

Abbreviations and Acronyms   AF   atrial fibrillation   ICa,L   L-type calcium current   Ito   transient outward potassium current   mRNA   messenger ribonucleic acid   RA   right atria/atrial/atrium   RAP   rapid atrial pacing   RT-PCR   reverse transcription-polymerase chain reaction

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