Overexpression of cAMP-response element modulator causes abnormal growth and development of the atrial myocardium resulting in a substrate for sustained atrial fibrillation in mice.

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 (<8weeks) 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.

• Authors: Paulus Kirchhof, Eloi Marijon, Larissa Fabritz, Na Li, Wei Wang, Tiannan Wang, Kirsten Schulte, Juliane Hanstein, Jan S Schulte, Mathis Vogel, Nathalie Mougenot, Sandra Laakmann, Lisa Fortmueller, Jens Eckstein, Sander Verheule, Sven Kaese, Ariane Staab, Stephanie Grote-Wessels, Ulrich Schotten, Ghassan Moubarak, Xander H T Wehrens, Wilhelm Schmitz, Stéphane Hatem, Frank Ulrich Müller
• Journal: International journal of cardiology (Int J Cardiol) Vol. 166 Issue 2 Pg. 366-74 (Jun 20 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 22093963 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Crem protein, mouse
• Cyclic AMP Response Element Modulator

Topics

• Animals
• Atrial Fibrillation (metabolism, pathology, physiopathology)
• Cyclic AMP Response Element Modulator (biosynthesis)
• Gene Expression Regulation
• Heart Atria (metabolism, pathology, physiopathology)
• Mice
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• Organ Culture Techniques
• Time Factors