Abstract
Background and methods
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice.
The substrate of AF is composed of a complex interplay between structural and functional
changes of the atrial myocardium often preceding the occurrence of persistent AF.
However, there are only few animal models reproducing the slow progression of the
AF substrate to the spontaneous occurrence of the arrhythmia. Transgenic mice (TG)
with cardiomyocyte-directed expression of CREM-IbΔC-X, an isoform of transcription
factor CREM, develop atrial dilatation and spontaneous-onset AF. Here we tested the
hypothesis that TG mice develop an arrhythmogenic substrate preceding AF using physiological
and biochemical techniques.
Results
Overexpression of CREM-IbΔC-X in young TG mice (<8 weeks) led to atrial dilatation combined with distension of myocardium, elongated
myocytes, little fibrosis, down-regulation of connexin 40, loss of excitability with
a number of depolarized myocytes, atrial ectopies and inducibility of AF. These abnormalities
continuously progressed with age resulting in interatrial conduction block, increased
atrial conduction heterogeneity, leaky sarcoplasmic reticulum calcium stores and the
spontaneous occurrence of paroxysmal and later persistent AF. This distinct atrial
remodelling was associated with a pattern of non-regulated and up-regulated marker
genes of myocardial hypertrophy and fibrosis.
Conclusions
Expression of CREM-IbΔC-X in TG hearts evokes abnormal growth and development of the
atria preceding conduction abnormalities and altered calcium homeostasis and the development
of spontaneous and persistent AF. We conclude that transcription factor CREM is an
important regulator of atrial growth implicated in the development of an arrhythmogenic
substrate in TG mice.
Keywords
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Article info
Publication history
Published online: November 17, 2011
Accepted:
October 18,
2011
Received:
September 21,
2011
Identification
Copyright
© 2011 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.