Abstract 2895: Atrial Arrhythmia in Connexin 40 Deficient and Connexin 43 Mutant Mice
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in general practice. Re-entrant mechanisms of AF are promoted by slowing of cardiac conduction. Cell-to-cell cardiac impulse propagation depends on communication through gap junction channels which are composed of connexins (Cx’s). Previous studies in cultured neonatal atrial strands showed that reduced Cx40 content increased atrial conduction velocity while reduced Cx43 decreased conduction velocity. However, the role of connexins in AF remains controversial as both increases and decreases in Cx40 and Cx43 have been found in animal models and patients with AF. To determine the role of altered connexin content in AF we examined mice deficient in Cx40 (Cx40−/−) and a dominant negative Cx43 G60S (Cx43G60S) mutant mouse that has reduced cardiac Cx43.
Objective: This study tested the hypothesis that AF susceptibility would be enhanced in the Cx43G60S mutant but not Cx40−/− mice.
Methods: In vivo intracardiac electrophysiological pacing studies were performed in 6 month old male Cx40−/−, Cx43G60S and wild type (WT) anaesthetized mice. AF susceptibility was determined with programmed electrical stimulation using 1 extra stimulus (PES-S2), burst pacing (400ms burst, 2 ms pulses, 50 Hz) and intraperitoneal injection of carbachol (0.5 mg/kg).
Results: Atrial effective refractory periods were longer in the high right atrium (HRA) compared to the mid right atrium (MRA) (32.2±1.2 vs 24.2±0.9, P<0.05) but did not differ between WT, Cx40−/− and Cx43G60S mutant mice. Cx43G60S mutant mice were more susceptible to sustained AF (duration >60 sec, max 32 min, 7/7) compared to WT mice (1/15) with PES-S2. Cx40−/− mice were not susceptible to AF (0/9) with either PES-S2 or burst pacing. Carbachol enhanced AF susceptibility in WT (7/12) but not Cx40−/− mice. Unidirectional conduction block from the MRA to HRA was seen in AF in 4/7 Cx43G60S mutant mice.
Conclusions: These results demonstrate the importance of reductions in Cx43 in AF mechanisms. PES-S2 induction and unidirectional conduction block during AF suggests a re-entrant mechanism of in Cx43G60S mice. In contrast, the results demonstrate that a homogeneous reduction in Cx40 is antiarrhythmic.