Research Article| Volume 166, ISSUE 2, P366-374, June 20, 2013

Download started.


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

Published:November 17, 2011DOI:


      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.


      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.


      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.


      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 access
      One-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 to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Mayr B.
        • Montminy M.
        Transcriptional regulation by the phosphorylation-dependent factor CREB.
        Nat Rev Mol Cell Biol. 2001; 2: 599-609
        • Müller F.U.
        • Bokník P.
        • Horst A.
        • et al.
        cAMP response element binding protein is expressed and phosphorylated in the human heart.
        Circulation. 1995; 92: 2041-2043
        • Müller F.U.
        • Bokník P.
        • Knapp J.
        • et al.
        Identification and expression of a novel isoform of cAMP response element modulator in the human heart.
        FASEB J. 1998; 12: 1191-1199
        • Lewin G.
        • Matus M.
        • Basu A.
        • et al.
        Critical role of transcription factor cyclic AMP response element modulator in beta1-adrenoceptor-mediated cardiac dysfunction.
        Circulation. 2009; 119: 79-88
        • Müller F.U.
        • Lewin G.
        • Baba H.A.
        • et al.
        Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice.
        J Biol Chem. 2005; 280: 6906-6914
        • Camm A.J.
        • Kirchhof P.
        • Lip G.Y.
        • et al.
        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
        • Nattel S.
        • Duker G.
        • Carlsson L.
        Model systems for the discovery and development of antiarrhythmic drugs.
        Prog Biophys Mol Biol. 2008; 98: 328-339
        • Kirchhof P.
        • Fabritz L.
        • Zwiener M.
        • et al.
        Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.
        Circulation. 2006; 114: 1799-1806
        • Fabritz L.
        • Kirchhof P.
        • Fortmüller L.
        • et al.
        Gene dose-dependent atrial arrhythmias, heart block and atrial brady-cardiomyopathy in mice overexpressing the A3-adenosine receptor.
        Cardiovasc Res. 2004; 62: 500-508
        • Wittköpper K.
        • Fabritz L.
        • Neef S.
        • et al.
        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
        • Rothaus K.
        • Jiang X.
        • Waldeyer T.
        • Fabritz L.
        • Vogel M.
        • Kirchhof P.
        Data mining for detecting disturbances in heart rhythm.
        in: International Conference on Machine Learning and Cybernetics, Kumming, China. 2008: 3211-3216
        • Abi-Char J.
        • Maguy A.
        • Coulombe A.
        • et al.
        Membrane cholesterol modulates Kv1.5 potassium channel distribution and function in rat cardiomyocytes.
        J Physiol. 2007; 582: 1205-1217
        • Blana A.
        • Kaese S.
        • Fortmüller L.
        • et al.
        A knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.
        Heart Rhythm. 2010; 7: 1862-1869
        • Milliez P.
        • Deangelis N.
        • Rucker-Martin C.
        • et al.
        Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction.
        Eur Heart J. 2005; 26: 2193-2199
        • Sood S.
        • Chelu M.G.
        • van Oort R.J.
        • et al.
        Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation.
        Heart Rhythm. 2008; 5: 1047-1054
        • Sarma S.
        • Li N.
        • van Oort R.J.
        • Reynolds C.
        • Skapura D.G.
        • Wehrens X.H.
        Genetic inhibition of PKA phosphorylation of Ryr2 prevents dystrophic cardiomyopathy.
        Proc Natl Acad Sci U S A. 2010; 107: 13165-13170
        • Pfaffl M.W.
        • Horgan G.W.
        • Dempfle L.
        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
        • Boyden P.A.
        • Tilley L.P.
        • Pham T.D.
        • Liu S.K.
        • Fenoglic Jr., J.J.
        • Wit A.L.
        Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis.
        Am J Cardiol. 1982; 49: 1896-1908
        • Boyden P.A.
        • Tilley L.P.
        • Albala A.
        • Liu S.-K.
        • Fenoglio Jr., J.J.
        • Wit A.L.
        Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease.
        Circulation. 1984; 69: 1036-1047
        • Mary-Rabine L.
        • Albert A.
        • Pham T.D.
        • et al.
        The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure.
        Circ Res. 1983; 52: 188-199
        • Deroubaix E.
        • Folliguet T.
        • Rucker-Martin C.
        • et al.
        Moderate and chronic hemodynamic overload of sheep atria induces reversible cellular electrophysiologic abnormalities and atrial vulnerability.
        J Am Coll Cardiol. 2004; 44: 1918-1926
        • Boutjdir M.
        • Le Heuzey J.Y.
        • Lavergne T.
        • et al.
        Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia?.
        Pacing Clin Electrophysiol. 1986; 9: 1095-1100
        • Hagendorff A.
        • Schumacher B.
        • Kirchhoff S.
        • Lüderitz B.
        • Willecke K.
        Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation.
        Circulation. 1999; 99: 1508-1515
        • Verheule S.
        • van Batenburg C.A.
        • Coenjaerts F.E.
        • Kirchhoff S.
        • Willecke K.
        • Jongsma H.J.
        Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40.
        J Cardiovasc Electrophysiol. 1999; 10: 1380-1389
        • Bagwe S.
        • Berenfeld O.
        • Vaidya D.
        • Morley G.E.
        • Jalife J.
        Altered right atrial excitation and propagation in connexin 40 knockout mice.
        Circulation. 2005; 112: 2245-2253
        • Chelu M.G.
        • Satyam S.
        • Sood S.
        • et al.
        Calmodulin kinase II-mediated sarcoplasmatic reticulum Ca2+ leak promotes atrial fibrillation in mice.
        J Clin Invest. 2009; 119: 1940-1951
        • Iribe G.
        • Ward C.W.
        • Camelliti P.
        • et al.
        Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate.
        Circ Res. 2009; 104: 787-795
        • Kong C.R.
        • Bursac N.
        • Tung L.
        Mechanoelectrical excitation by fluid jets in monolayers of cultured cardiac myocytes.
        J Appl Physiol. 2005; 98: 2328-2336
        • Zhang X.
        • Odom D.T.
        • Koo S.H.
        • et al.
        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
        • Jin C.
        • Ugai H.
        • Song J.
        • et al.
        Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.
        FEBS Lett. 2001; 489: 34-41
        • Kehat I.
        • Heinrich R.
        • Ben-Izhak O.
        • Miyazaki H.
        • Gutkind J.S.
        • Aronheim A.
        Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation.
        Cardiovasc Res. 2006; 70: 543-554
        • Donald J.E.
        • Shakhnovich E.I.
        Predicting specificity-determining residues in two large eukaryotic transcription factor families.
        Nucleic Acids Res. 2005; 33: 4455-4465
        • Barth A.S.
        • Merk S.
        • Arnoldi E.
        • et al.
        Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature.
        Circ Res. 2005; 96: 1022-1029

      Linked Article