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(Circulation. 2005;112:2245-2253.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Altered Right Atrial Excitation and Propagation in Connexin40 Knockout Mice

Suveer Bagwe, MD, MSc; Omer Berenfeld, PhD; Dhananjay Vaidya, MPH, PhD; Gregory E. Morley, PhD; José Jalife, MD

From the Institute for Cardiovascular Research, State University of New York Upstate Medical University, Syracuse.

Correspondence to José Jalife, MD, Department of Pharmacology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210. E-mail jalifej{at}upstate.edu

Received December 2, 2004; revision received July 11, 2005; accepted July 20, 2005.

Background— Intercellular coupling via connexin40 (Cx40) gap junction channels is an important determinant of impulse propagation in the atria.

Methods and Results— We studied the role of Cx40 in intra-atrial excitation and propagation in wild-type (Cx40^+/+) and knockout (Cx40^–/–) mice using high-resolution, dual-wavelength optical mapping. On ECG, the P wave was significantly prolonged in Cx40^–/– mice (13.4±0.5 versus 11.4±0.3 ms in Cx40^+/+). In Cx40^+/+ hearts, spontaneous right atrial (RA) activation showed a focal breakthrough at the junction of the right superior vena cava, sulcus terminalis, and RA free wall, corresponding to the location of the sinoatrial node. In contrast, Cx40^–/– hearts displayed ectopic breakthrough sites at the base of the sulcus terminalis, RA free wall, and right superior vena cava. Progressive ablation of such sites in 4 Cx40^–/– mice resulted in ectopic focus migration and cycle length prolongation. In all Cx40^–/– hearts the focus ultimately shifted to the sinoatrial node at a very prolonged cycle length (initial ectopic cycle length, 182±20 ms; postablation sinus cycle length, 387±44 ms). In a second group of experiments, epicardial pacing at 10 Hz revealed slower conduction in the RA free wall of 5 Cx40^–/– hearts than in 5 Cx40^+/+ hearts (0.61±0.07 versus 0.94±0.07 m/s; P<0.05). Dominant frequency analysis in Cx40^–/– RA demonstrated significant reduction in the area of 1:1 conduction at 16 Hz (40±10% versus 69±5% in Cx40^+/+) and 25 Hz (36±11% versus 65±9% in Cx40^+/+).

Conclusions— This is the first demonstration of intra-atrial block, ectopic rhythms, and altered atrial propagation in the RA of Cx40^–/– mice.

Key Words: atrium • conduction • connexins • Fourier analysis • sinoatrial node

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