Altered right atrial excitation and propagation in connexin40 knockout mice

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.