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PRECLINICAL STUDY

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

Manuscript received August 1, 2005; revised manuscript received December 12, 2005, accepted January 5, 2006.

^_* Reprint requests and correspondence: Dr. Sanjiv M. Narayan, Director of Electrophysiology, VA Medical Center, Co-Director, Electrophysiology Training Program, University of California, San Diego, Cardiology 111A, 3350 La Jolla Village Drive, San Diego, California 92161. (Email: snarayan{at}ucsd.edu).

OBJECTIVES: 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.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Abbreviations and Acronyms   ACVI = adenylyl cyclase type VI   AH = atrial-to-His   ANOVA = analysis of variance   AV = atrioventricular   AVERP = atrioventricular nodal effective refractory period   ßAR = beta-adrenergic receptor   cAMP = cyclic adenosine monophosphate   CHF = congestive heart failure   CL = cycle length   CSNRT = corrected sinus node recovery time   ECG = electrocardiogram   EPS = electrophysiologic study   ERP = effective refractory period   MHC = major histocompatibility complex   SNRT = sinus node recovery time   VA = ventriculo-atrial

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