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Am J Physiol Heart Circ Physiol (November 22, 2006). doi:10.1152/ajpheart.00285.2006
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Submitted on March 17, 2006
Accepted on November 20, 2006

Downregulation of Connexin40 and Increased Prevalence of Atrial Arrhythmias in Transgenic Mice with Cardiac Restricted Overexpression of Tumor Necrosis Factor

Sam E. Sawaya1, Yadavendra S. Rajawat2, Tapan G. Rami2, Gabor Szalai3, Robert L. Price4, Natarajan Sivasubramanian2, Douglas L. Mann2, and Dirar S. Khoury2*

1 Medicine-Cardiology, Baylor College of Medicine, houston, Texas, United States
2 Medicine-Cardiology, Baylor College of Medicine, Houston, Texas, United States
3 Houston, Texas, United States; Medicine-Cardiology, Baylor College of Medicine, Houston, Texas, United States
4 Cell and Developmental Biology and Anatomy, University of South Carolina, Columbia, South Carolina, United States

* To whom correspondence should be addressed. E-mail: dkhoury{at}tmh.tmc.edu.

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 5 out of 8 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 Cx40 that was associated with an increased prevalence of atrial arrhythmias.




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