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Cardiac-Directed Expression of Adenylyl Cyclase VI Facilitates Atrioventricular Nodal Conduction

Ashwani Sastry, BS^_*, Elizabeth Arnold, BA^_*, Hunaid Gurji, BS^_*,, Atsushi Iwasa, MD^_*,, Hanh Bui, MD^_*,, Alborz Hassankhani, MD, PhD^_*,, Hemal H. Patel, PhD^_*, James R. Feramisco, PhD^_*, David M. Roth, MD^_*,, N. Chin Lai, PhD, H. Kirk Hammond, MD^_*, and Sanjiv M. Narayan, MB, MD^_*,,_*

^_* University of California, San Diego, California
Veterans Affairs San Diego Healthcare System, San Diego, California

View larger version (94K): [in a new window]   Figure 1 Surgical field and electrophysiology catheter. (A) View of right external jugular cutdown and 1.7-F electrophysiology catheter in an anesthetized mouse. (B) Close-up of venous cutdown with proximal and distal sutures. The venotomy is made between these sutures, and the catheter is advanced to the atrioventricular junction and then sutured in place.

View larger version (17K): [in a new window]   Figure 2 Electrocardiogram and intracardiac electrograms during sinus rhythm, showing atrial, His, and ventricular electrograms from an octapolar catheter at the atrioventricular junction. Bipoles are labeled Intra-P (proximal, atrial), Intra-3 (atrioventricular junction), Intra-2 (His position), and Intra-D (distal, ventricular), respectively. Scale markings are in ms and intervals are marked. AH = atrial-to-His; HV = His-to-ventricular.

View larger version (14K): [in a new window]   Figure 3 Atrioventricular (AV) conduction and cycle length. Atrioventricular intervals were shorter in adenylyl cyclase type VI (ACVI) mice than in controls for a range of cycle lengths. The p value from analysis of variance; mean values ± 1 SEM are shown.

View larger version (23K): [in a new window]   Figure 4 Atrioventricular nodal Wenckebach during atrial pacing at cycle length 120 ms, showing atrial-to-His (AH) Wenckebach (intervals marked). Bipoles and timescale are labeled as in Figure 2.

View larger version (31K): [in a new window]   Figure 5 (A) Transient accelerated junctional rhythm. Episodes were of short duration (lasting seconds), self-limited, and seen in 1 animal from each group. (B) Transient atrial tachycardia. This rhythm was observed in a control-group mouse (cycle length 36 ms), likely induced by atrial pacing within the vulnerable period of the preceding native P-wave (labeled *). Note accelerated and variable ventricular rate during tachycardia. This finding was not reproduced and was seen only in this mouse. Bipoles and timescale are labeled as in Figure 2.

View larger version (128K): [in a new window]   Figure 6 Expression of ACVI in AV node. (A) 10x images of AV node region in heart from a mouse with cardiac-directed expression of ACVI. Green indicates staining for Cx45, a marker for AV nodal tissue; red indicates ACV/VI protein; overlap image (right) indicates co-expression of Cx45 and ACV/VI. (B) 60x images of area contained in white box in (A). There is considerable co-localization of Cx45 AV nodal stain with ACV/VI. (C) 60x image of ACVI and transgene-negative sibling mouse (control); heart sections exposed to ACV/VI antibodies show increased ACVI expression compared to heart sections from transgene-negative sibling. White bar lengths are (A) 100 µm; (B) 20 µm; (C) 20 µm. Abbreviations as in Figures 2 and 3.