Atrial fibrillation is the most common sustained arrhythmia in clinical practice. Atrial dilatation is often associated with atrial fibrillation, but it appears to be both the cause and a consequence of the arrhythmia. Prospective studies have showed that left atrial enlargement is an independent risk factor for the development of Atrial fibrillation. Atrial fibrillation is commonly initiated in the left atrium. The underlying molecular mechanisms responsible for atrial dilatation are largely unknown.

Accumulating evidence suggests that nuclear transcription factors from the basic leucine zipper (bZIP) family play an important role in cardiac development and function. This class includes the CREB/ATF family of transcription factors, namely CREB, CREM (cAMP response element modulator), ATF, and the related AP-1 and C/EBP families. An effort has been made to elucidate the role of specific bZIP members in the heart. Unfortunately, little insight could be gained from knockout experiments, either due to embryonic lethal phenotypes or functional compensation by other bZIP family members.

In order to try and characterize this pathway we have expressed the potent bZIP inhibitor protein, Jun dimerization protein 2 (JDP2), specifically in the mouse heart in a temporally controlled manner. Expression of JDP2 resulted in massive bi-atrial dilatation, loss of connexin 40 (Cx40), connexin43 (Cx43) and myosin light chain 2 (MLC2a) expression, atrio-ventricular conduction defects, and a lethal phenotype. All these effects were independent of any developmental events, and were totally reversible upon abolishing the bZIP inhibition. The results of this study suggest that bZIP inhibition is sufficient to cause atrial dilation, that this dilatation is acquired postnatally, and is reversible.

Few other transgenic models also resulted in atrial hypertrophy. This includes myocardial over-expression of angiotensin receptor and the ATF3 transcription factor. ATF3 is highly homologous to JDP2 sharing 90% identity within the basic leucine zipper DNA dimerization domain. Likewise, cardiac over-expression of members of the angiotensin (AT1) receptor signaling pathway resulted in a similar phenotype of massive bi-atrial dilatation and conduction defects without significant ventricular pathology. We focused our attention to study the possible signaling pathway initiating from the Renin-angiotensin system to ATF3. Indeed, acute injection of angiotensin II results in potentiation of ATF3 expression. The physiological relevance of ATF3 atrial expression and potential ATF3 target genes are currently under investigation.