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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to International Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Transcriptional regulation by the phosphorylation-dependent factor CREB.Nat Rev Mol Cell Biol. 2001; 2: 599-609
- cAMP response element binding protein is expressed and phosphorylated in the human heart.Circulation. 1995; 92: 2041-2043
- Identification and expression of a novel isoform of cAMP response element modulator in the human heart.FASEB J. 1998; 12: 1191-1199
- Critical role of transcription factor cyclic AMP response element modulator in beta1-adrenoceptor-mediated cardiac dysfunction.Circulation. 2009; 119: 79-88
- Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice.J Biol Chem. 2005; 280: 6906-6914
- Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC).Eur Heart J. 2010; 31: 2369-2429
- Model systems for the discovery and development of antiarrhythmic drugs.Prog Biophys Mol Biol. 2008; 98: 328-339
- Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.Circulation. 2006; 114: 1799-1806
- Gene dose-dependent atrial arrhythmias, heart block and atrial brady-cardiomyopathy in mice overexpressing the A3-adenosine receptor.Cardiovasc Res. 2004; 62: 500-508
- Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.J Clin Invest. 2010; 120: 617-626
- Data mining for detecting disturbances in heart rhythm.in: International Conference on Machine Learning and Cybernetics, Kumming, China. 2008: 3211-3216
- Membrane cholesterol modulates Kv1.5 potassium channel distribution and function in rat cardiomyocytes.J Physiol. 2007; 582: 1205-1217
- A knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.Heart Rhythm. 2010; 7: 1862-1869
- Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction.Eur Heart J. 2005; 26: 2193-2199
- Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation.Heart Rhythm. 2008; 5: 1047-1054
- Genetic inhibition of PKA phosphorylation of Ryr2 prevents dystrophic cardiomyopathy.Proc Natl Acad Sci U S A. 2010; 107: 13165-13170
- Relative Expression Software Tool (Rest) for group wise comparison and statistical analysis of relative expression results in real-time PCR.Nucleic Acids Res. 2002; 30: E36
- Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis.Am J Cardiol. 1982; 49: 1896-1908
- Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease.Circulation. 1984; 69: 1036-1047
- The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure.Circ Res. 1983; 52: 188-199
- Moderate and chronic hemodynamic overload of sheep atria induces reversible cellular electrophysiologic abnormalities and atrial vulnerability.J Am Coll Cardiol. 2004; 44: 1918-1926
- Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia?.Pacing Clin Electrophysiol. 1986; 9: 1095-1100
- Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation.Circulation. 1999; 99: 1508-1515
- Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40.J Cardiovasc Electrophysiol. 1999; 10: 1380-1389
- Altered right atrial excitation and propagation in connexin 40 knockout mice.Circulation. 2005; 112: 2245-2253
- Calmodulin kinase II-mediated sarcoplasmatic reticulum Ca2+ leak promotes atrial fibrillation in mice.J Clin Invest. 2009; 119: 1940-1951
- Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate.Circ Res. 2009; 104: 787-795
- Mechanoelectrical excitation by fluid jets in monolayers of cultured cardiac myocytes.J Appl Physiol. 2005; 98: 2328-2336
- Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues.Proc Natl Acad Sci U S A. 2005; 102: 4459-4464
- Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.FEBS Lett. 2001; 489: 34-41
- Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation.Cardiovasc Res. 2006; 70: 543-554
- Predicting specificity-determining residues in two large eukaryotic transcription factor families.Nucleic Acids Res. 2005; 33: 4455-4465
- Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature.Circ Res. 2005; 96: 1022-1029
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.
