Abstract
The purpose of this study was to test the hypothesis that cardiac-directed expression of adenylyl cyclase VI (AC(VI)) facilitates atrioventricular (AV) nodal conduction. Cardiac-directed expression of AC(VI), unlike other strategies to increase cyclic adenosine monophosphate generation, reduces mortality in murine cardiomyopathy. Recent reports suggest that AC(VI) expression may also protect against lethal bradycardia. We performed immunofluorescence staining for AC(VI) in the AV node of transgenic mice. We then performed electrophysiologic studies (EPSs) using a 1.7-F octapolar catheter at the AV junction in 11 transgenic AC(VI) mice and 14 control mice. Immunofluorescence staining revealed increased AC(VI) expression in the AV node of transgenic mice versus controls. During EPS, AV intervals approximated PR intervals (R2 = 0.99) and related linearly to atrial-to-His intervals (R2 = 0.98; both p < 0.0001). Thus, we studied AV intervals to avoid electrocardiogram pacing artifacts and inconsistent inscription of His bundle electrograms. At baseline, AC(VI) mice had shorter AV intervals (47 +/- 9 ms) than controls (57 +/- 11 ms; p = 0.02), despite similar sinus rates. In pacing, AV intervals were shorter in AC(VI) mice than controls for a wide cycle-length range (p < 0.01). The AC(VI) mice also had shorter AV Wenckebach cycle lengths (AC(VI): 114 +/- 12 ms; control: 131 +/- 28 ms; p = 0.05) and ventriculo-atrial effective refractory periods (AC(VI): 97 +/- 21 ms; control: 127 +/- 15 ms; p = 0.05). We observed no differences between groups in sinus node function, and ventricular arrhythmias were not inducible. Cardiac-directed expression of AC(VI) facilitates AV nodal conduction without altering sinus node function. These results suggest the need to define a role for AC(VI) gene transfer in treating diseases of AV conduction.
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