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.