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Am J Physiol Heart Circ Physiol 292: H1561-H1567, 2007. First published November 22, 2006; doi:10.1152/ajpheart.00285.2006
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Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor

Sam E. Sawaya,1 Yadavendra S. Rajawat,1 Tapan G. Rami,1 Gabor Szalai,1 Robert L. Price,2 Natarajan Sivasubramanian,1 Douglas L. Mann,1 and Dirar S. Khoury1

1Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, and 2Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina

Submitted 17 March 2006 ; accepted in final form 20 November 2006

Atrial arrhythmias, primarily atrial fibrillation, have been independently associated with structural remodeling and with inflammation. We hypothesized that sustained inflammatory signaling by tumor necrosis factor (TNF) would lead to alterations both in underlying atrial myocardial structure and in atrial electrical conduction. We performed ECG recording, intracardiac electrophysiology studies, epicardial mapping, and connexin immunohistochemical analyses on transgenic mice with targeted overexpression of TNF in the cardiac compartment (MHCsTNF) and on wild-type (WT) control mice (age 8–16 wk). Atrial and ventricular conduction abnormalities were always evident on ECG in MHCsTNF mice, including a shortened atrioventricular interval with a wide QRS duration secondary to junctional rhythm. Supraventricular arrhythmias were observed in five of eight MHCsTNF mice, whereas none of the mice demonstrated ventricular arrhythmias. No arrhythmias were observed in WT mice. Left ventricular conduction velocity during apical pacing was similar between the two mouse groups. Connexin40 was significantly downregulated in MHCsTNF mice. In contrast, connexin43 density was not significantly altered in MHCsTNF mice, but rather dispersed away from the intercalated disks. In conclusion, sustained inflammatory signaling contributed to atrial structural remodeling and downregulation of connexin40 that was associated with an increased prevalence of atrial arrhythmias.

atrial fibrillation; electrophysiology; heart failure


Address for reprint requests and other correspondence: D. S. Khoury, Methodist DeBakey Heart Center, The Methodist Hospital, 6565 Fannin St, F764, Houston, TX 77030 (e-mail:dkhoury{at}tmh.tmc.edu)




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