Dedifferentiation of atrial myocytes during atrial fibrillation: role of fibroblast proliferation in vitro.

Objectives: Severe myocyte alterations, characterized by enlarged myocytes and myolysis, is observed in fibrillating and dilated atria and contributes to atrial fibrillation. The aim of this study was to determine the nature of this cellular remodeling process and factors involved in its regulation.

Methods: In vivo, contractile proteins were studied in 24 human right atrial specimens by means of immunohistochemical techniques. In an attempt to reproduce in vitro the myocyte remodeling and to study its regulation, human atrial myocytes were cultured (n=27) and analyzed immunocytochemically; intracellular Ca(2+) transients (Ca(i)-tr) in response to electrical stimulation were monitored using Fura-2/AM.

Results: In diseased specimens, sarcomeres, seen at the periphery of myolytic myocytes, stained positively with antibodies against sarcomeric proteins of the Z-band (alpha-actinin and titin epitope T12) but not with antibodies against titin epitope T11 (I-band) or desmin (intermediate filament). beta-myosin heavy chain (MHC) and smooth muscle alpha-actin, two proteins of the fetal program, were re-expressed. In culture, diseased myocytes also showed myolysis and glycogen accumulation; their sarcomeres stained positively with anti-alpha-actinin, anti-T12, anti-beta-MHC and anti-smooth muscle alpha-actin but not with anti-titin T11 or anti-desmin antibodies. At confluence, myocytes regained a normal sarcomeric apparatus and were excitable, as shown by electrical Ca(i)-tr triggering. This redifferentiation process was inhibited by fibroblast proliferation.

Conclusion: In diseased atria, myolytic myocytes are in a dedifferentiated state resembling that of immature muscle cells. In vitro, fibroblast proliferation prevents the reversibility of this cellular alteration.