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Cardiovascular Research 2002 55(1):38-52; doi:10.1016/S0008-6363(02)00338-3
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

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

Catherine Rücker-Martina,*, Françoise Peckerb, David Godreauc and Stéphane N Hatemc

aCNRS ESA 8078, Physiologie Cardiovasculaire et Thymique, Hôpital Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France
bINSERM Unité 99, Hôpital Henri Mondor, 94010 Créteil, France
cINSERM Unité 460 and Service de Chirurgie Cardiaque, Hôpital and Faculté de Médecine Xavier Bichat, 75018 Paris, France

francoise.pecker{at}im3.inserm.fr

hatem{at}bichat.inserm.fr

* Corresponding author. Tel.: +33-1-4631-5611; fax: +33-1-4630-4564 catherine.rucker{at}ccml.u-psud.fr

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 Ca2+ transients (Cai-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). β-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-β-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 Cai-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.

KEYWORDS Arrhythmia (mechanisms); Atrial function; Fibrosis; Histo(patho)logy; Myocytes; Remodeling


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